[ { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/w52af-s8425", "eprint_id": 96306, "eprint_status": "archive", "datestamp": "2023-08-22 08:27:20", "lastmod": "2023-12-22 23:11:34", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Olariu-Annell-Victor", "name": { "family": "Olariu", "given": "Victor" }, "orcid": "0000-0002-4579-9982" }, { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary A." }, "orcid": "0000-0002-3136-2181" }, { "id": "Krupinski-Pawel", "name": { "family": "Krupinski", "given": "Pawel" }, "orcid": "0000-0002-9450-8272" }, { "id": "Zhou-Wen", "name": { "family": "Zhou", "given": "Wen" }, "orcid": "0000-0003-0357-2744" }, { "id": "Deichmann-Julia", "name": { "family": "Deichmann", "given": "Julia" }, "orcid": "0000-0003-1364-908X" }, { "id": "Andersson-Emil", "name": { "family": "Andersson", "given": "Emil" }, "orcid": "0000-0001-6523-4973" }, { "id": "Rothenberg-E-V", "name": { "family": "Rothenberg", "given": "Ellen V." }, "orcid": "0000-0002-3901-347X" }, { "id": "Peterson-Carsten", "name": { "family": "Peterson", "given": "Carsten" }, "orcid": "0000-0001-7362-2191" } ] }, "title": "Multi-scale Dynamical Modeling of T Cell Development from an Early Thymic Progenitor State to Lineage Commitment", "ispublished": "pub", "full_text_status": "public", "keywords": "T cell development; transcriptional modeling; epigenetic modeling; population modeling; stochastic simulations; single-cell measurements; proliferation measurements; kinetic measurements; experimental validations", "note": "\u00a9 2020 The Author(s). Under a Creative Commons license - Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0). \n\nReceived 15 October 2019, Revised 24 April 2020, Accepted 18 December 2020, Available online 12 January 2021. \n\nThe authors thank Dr. Long Cai for support for the smFISH analysis; Dr. Jeffrey Longmate for data analysis; Dr. Hao Yuan Kueh for helpful discussions and advice on imaging and analysis; Kenneth Ng for technical help; Diana Perez, Jamie Tijerina, and Rochelle Diamond of the Caltech Flow Cytometry Facility for fluorescence-activated cell sorting (FACS); and Dr. Andreas Collazo and the Caltech Biological Imaging Facility for microscopy assistance. The authors gratefully acknowledge the support of the US National Institutes of Health (USPHS grant R01HL119102 to E.V.R. and C.P.) and the Albert Billings Ruddock Professorship (to E.V.R.). \n\nAuthor Contributions. V.O., M.A.Y., E.V.R., and C.P. designed the study. V.O., M.A.Y., E.V.R., and C.P. wrote most of the manuscript. M.A.Y. performed the CTV and kinetics experiments. W.Z. performed the FISH experiments and wrote part of the manuscript. V.O. developed the transcriptional and epigenetic models and analyzed the data. P.K. developed the population model. E.A. conducted parameter optimization and confidence bounds calculations. J.D. implemented the pseudo-time-series and multi-scale models. \n\nThe modeling results shown in Figures 1, 4, and 5 along with the ones in the Figures S2, S4, and S7 were obtained using MATLAB version 9..3.0.713579 R (2017b), The Mathworks, Inc. Available at https://www.mathworks.com. \n\nThe authors declare no competing interests.\n\n
Published - 1-s2.0-S2211124720316119-main.pdf
Accepted Version - nihms-1670076.pdf
Submitted - 667709.full.pdf
Supplemental Material - 1-s2.0-S2211124720316119-mmc1.pdf
Supplemental Material - 1-s2.0-S2211124720316119-mmc2.xlsx
", "abstract": "Intrathymic development of committed progenitor (pro)-T cells from multipotent hematopoietic precursors offers an opportunity to dissect the molecular circuitry establishing cell identity in response to environmental signals. This transition encompasses programmed shutoff of stem/progenitor genes, upregulation of T cell specification genes, proliferation, and ultimately commitment. To explain these features in light of reported cis-acting chromatin effects and experimental kinetic data, we develop a three-level dynamic model of commitment based upon regulation of the commitment-linked gene Bcl11b. The levels are (1) a core gene regulatory network (GRN) architecture from transcription factor (TF) perturbation data, (2) a stochastically controlled chromatin-state gate, and (3) a single-cell proliferation model validated by experimental clonal growth and commitment kinetic assays. Using RNA fluorescence in situ hybridization (FISH) measurements of genes encoding key TFs and measured bulk population dynamics, this single-cell model predicts state-switching kinetics validated by measured clonal proliferation and commitment times. The resulting multi-scale model provides a mechanistic framework for dissecting commitment dynamics.", "date": "2021-01-12", "date_type": "published", "publication": "Cell Reports", "volume": "34", "number": "2", "publisher": "Cell Press", "pagerange": "Art. No. 108622", "id_number": "CaltechAUTHORS:20190612-072821066", "issn": "2211-1247", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20190612-072821066", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R01HL119102" }, { "agency": "Albert Billings Ruddock Professorship" } ] }, "local_group": { "items": [ { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1016/j.celrep.2020.108622", "pmcid": "PMC7943435", "primary_object": { "basename": "1-s2.0-S2211124720316119-main.pdf", "url": "https://authors.library.caltech.edu/records/w52af-s8425/files/1-s2.0-S2211124720316119-main.pdf" }, "related_objects": [ { "basename": "1-s2.0-S2211124720316119-mmc1.pdf", "url": "https://authors.library.caltech.edu/records/w52af-s8425/files/1-s2.0-S2211124720316119-mmc1.pdf" }, { "basename": "1-s2.0-S2211124720316119-mmc2.xlsx", "url": "https://authors.library.caltech.edu/records/w52af-s8425/files/1-s2.0-S2211124720316119-mmc2.xlsx" }, { "basename": "667709.full.pdf", "url": "https://authors.library.caltech.edu/records/w52af-s8425/files/667709.full.pdf" }, { "basename": "nihms-1670076.pdf", "url": "https://authors.library.caltech.edu/records/w52af-s8425/files/nihms-1670076.pdf" } ], "resource_type": "article", "pub_year": "2021", "author_list": "Olariu, Victor; Yui, Mary A.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/twh49-k4h37", "eprint_id": 100161, "eprint_status": "archive", "datestamp": "2023-08-22 04:47:34", "lastmod": "2023-10-18 19:08:25", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Rodriguez-Sonia", "name": { "family": "Rodriguez", "given": "Sonia" } }, { "id": "Abundis-Christina", "name": { "family": "Abundis", "given": "Christina" } }, { "id": "Boccalatte-Francesco", "name": { "family": "Boccalatte", "given": "Francesco" } }, { "id": "Mehrotra-Purvi", "name": { "family": "Mehrotra", "given": "Purvi" }, "orcid": "0000-0001-9369-5013" }, { "id": "Chiang-Mark-Y", "name": { "family": "Chiang", "given": "Mark Y." } }, { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary A." }, "orcid": "0000-0002-3136-2181" }, { "id": "Wang-Lin", "name": { "family": "Wang", "given": "Lin" } }, { "id": "Zhang-Huajia", "name": { "family": "Zhang", "given": "Huajia" } }, { "id": "Zollman-Amy", "name": { "family": "Zollman", "given": "Amy" } }, { "id": "Bonfim-Silva-Ricardo", "name": { "family": "Bonfim-Silva", "given": "Ricardo" } }, { "id": "Kloetgen-Andreas", "name": { "family": "Kloetgen", "given": "Andreas" } }, { "id": "Palmer-Joycelynne", "name": { "family": "Palmer", "given": "Joycelynne" } }, { "id": "Sandusky-George", "name": { "family": "Sandusky", "given": "George" } }, { "id": "Wunderlich-Mark", "name": { "family": "Wunderlich", "given": "Mark" } }, { "id": "Kaplan-Mark-H", "name": { "family": "Kaplan", "given": "Mark H." } }, { "id": "Mulloy-James-C", "name": { "family": "Mulloy", "given": "James C." } }, { "id": "Marcucci-Guido", "name": { "family": "Marcucci", "given": "Guido" } }, { "id": "Aifantis-Iannis", "name": { "family": "Aifantis", "given": "Iannis" } }, { "id": "Cardoso-Angelo-A", "name": { "family": "Cardoso", "given": "Angelo A." } }, { "id": "Carlesso-Nadia", "name": { "family": "Carlesso", "given": "Nadia" } } ] }, "title": "Therapeutic targeting of the E3 ubiquitin ligase SKP2 in T-ALL", "ispublished": "pub", "full_text_status": "public", "keywords": "Acute lymphocytic leukaemia; Targeted therapies", "note": "\u00a9 The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. \n\nReceived 23 April 2019; Revised 18 October 2019; Accepted 13 November 2019; Published 26 November 2019. \n\nWe thank the Flow Cytometry, In Vivo Therapeutics and Optical Imaging cores supported by Indiana Center for Excellence in Molecular Hematology (National Insitute of Diabetes and Digestive and Kidney Diseases grant P30 DK090948), and the ARC Core at City of Hope supported by the National Cancer Institute of the National Institutes of Health under grant number P30CA033572. Part of this work was supported by the Grace M. Showalter Trust (064727-00002B, SR). \n\nThe authors declare that they have no conflict of interest.\n\nPublished - s41375-019-0653-z.pdf
Supplemental Material - 41375_2019_653_MOESM1_ESM.docx
", "abstract": "Timed degradation of the cyclin-dependent kinase inhibitor p27^(Kip1) by the E3 ubiquitin ligase F-box protein SKP2 is critical for T-cell progression into cell cycle, coordinating proliferation and differentiation processes. SKP2 expression is regulated by mitogenic stimuli and by Notch signaling, a key pathway in T-cell development and in T-cell acute lymphoblastic leukemia (T-ALL); however, it is not known whether SKP2 plays a role in the development of T-ALL. Here, we determined that SKP2 function is relevant for T-ALL leukemogenesis, whereas is dispensable for T-cell development. Targeted inhibition of SKP2 by genetic deletion or pharmacological blockade markedly inhibited proliferation of human T-ALL cells in vitro and antagonized disease in vivo in murine and xenograft leukemia models, with little effect on normal tissues. We also demonstrate a novel feed forward feedback loop by which Notch and IL-7 signaling cooperatively converge on SKP2 induction and cell cycle activation. These studies show that the Notch/SKP2/p27^(Kip1) pathway plays a unique role in T-ALL development and provide a proof-of-concept for the use of SKP2 as a new therapeutic target in T-cell acute lymphoblastic leukemia (T-ALL).", "date": "2020-05", "date_type": "published", "publication": "Leukemia", "volume": "34", "number": "5", "publisher": "Nature Publishing Group", "pagerange": "1241-1252", "id_number": "CaltechAUTHORS:20191203-083909065", "issn": "0887-6924", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20191203-083909065", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "P30 DK090948" }, { "agency": "NIH", "grant_number": "P30CA033572" }, { "agency": "Grace M. Showalter Trust", "grant_number": "064727-00002B" } ] }, "doi": "10.1038/s41375-019-0653-z", "pmcid": "PMC7192844", "primary_object": { "basename": "41375_2019_653_MOESM1_ESM.docx", "url": "https://authors.library.caltech.edu/records/twh49-k4h37/files/41375_2019_653_MOESM1_ESM.docx" }, "related_objects": [ { "basename": "s41375-019-0653-z.pdf", "url": "https://authors.library.caltech.edu/records/twh49-k4h37/files/s41375-019-0653-z.pdf" } ], "resource_type": "article", "pub_year": "2020", "author_list": "Rodriguez, Sonia; Abundis, Christina; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/2qmmp-7q537", "eprint_id": 99303, "eprint_status": "archive", "datestamp": "2023-08-22 02:45:59", "lastmod": "2023-10-18 18:13:12", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Zhou-Wen", "name": { "family": "Zhou", "given": "Wen" }, "orcid": "0000-0003-0357-2744" }, { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary A." }, "orcid": "0000-0002-3136-2181" }, { "id": "Williams-B-A", "name": { "family": "Williams", "given": "Brian A." } }, { "id": "Yun-Jina", "name": { "family": "Yun", "given": "Jina" } }, { "id": "Wold-B-J", "name": { "family": "Wold", "given": "Barbara J." }, "orcid": "0000-0003-3235-8130" }, { "id": "Cai-Long", "name": { "family": "Cai", "given": "Long" }, "orcid": "0000-0002-7154-5361" }, { "id": "Rothenberg-E-V", "name": { "family": "Rothenberg", "given": "Ellen V." }, "orcid": "0000-0002-3901-347X" } ] }, "title": "Single-Cell Analysis Reveals Regulatory Gene Expression Dynamics Leading to Lineage Commitment in Early T Cell Development", "ispublished": "pub", "full_text_status": "public", "keywords": "T cell development; clonal development assay; single-cell RNA-seq; transcription factors; single-molecule in situ hybridization; developmental trajectory; model validation; RNA velocity; multilineage priming", "note": "\u00a9 2019 Elsevier Inc. \n\nReceived 6 May 2019, Revised 10 August 2019, Accepted 18 September 2019, Available online 16 October 2019. \n\nWe thank Jeff Park, Paul Rivaud, and Sisi Chen from the Caltech Single Cell Profiling and Engineering Center for help with the 10X Genomics samples; Andres Collazo and the Biological Imaging facility of Caltech for clonal live imaging support; Sean Upchurch and Diane Trout for C1 bioinformatic support; and members of the Rothenberg, Wold, and Cai labs for advice. We also thank Rochelle Diamond and members of the Caltech Flow Cytometry Facility for sorting, Ingrid Soto for mouse care, Igor Antoshechkin and Vijaya Kumar of the Caltech Jacobs Genomics Facility, and Xiwei Wu and the Integrative Genomic Core of City of Hope for Smartseq2 and bulk RNA sequencing. Support for this project came from USPHS grants (R01HL119102 and R01HD076915) to E.V.R., The Beckman Institute at Caltech for support of all the Caltech facilities, the Biology and Biological Engineering Division Bowes Leadership Chair Fund, the Louis A. Garfinkle Memorial Laboratory Fund, the Al Sherman Foundation, and the Albert Billings Ruddock Professorship to E.V.R. \n\nAuthor Contributions: W.Z. carried out most of the research and analysis and wrote the paper. M.A.Y. carried out and supervised research and wrote the paper. B.A.W. did C1 experiments, and J.Y. supported seqFISH work. B.J.W. and L.C. guided and supported research and edited the paper. E.V.R. supervised research, designed the project, and wrote the paper. \n\nDeclaration of Interests: L.C. is a co-founder and B.J.W. is a consultant of Spatial Genomics Inc. The authors declare no other competing interests.\n\nAccepted Version - nihms-1545118.pdf
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", "abstract": "Intrathymic T cell development converts multipotent precursors to committed pro-T cells, silencing progenitor genes while inducing T cell genes, but the underlying steps have remained obscure. Single-cell profiling was used to define the order of regulatory changes, employing single-cell RNA sequencing (scRNA-seq) for full-transcriptome analysis, plus sequential multiplexed single-molecule fluorescent in situ hybridization (seqFISH) to quantitate functionally important transcripts in intrathymic precursors. Single-cell cloning verified high T cell precursor frequency among the immunophenotypically defined \"early T cell precursor\" (ETP) population; a discrete committed granulocyte precursor subset was also distinguished. We established regulatory phenotypes of sequential ETP subsets, confirmed initial co-expression of progenitor with T cell specification genes, defined stage-specific relationships between cell cycle and differentiation, and generated a pseudotime model from ETP to T lineage commitment, supported by RNA velocity and transcription factor perturbations. This model was validated by developmental kinetics of ETP subsets at population and clonal levels. The results imply that multilineage priming is integral to T cell specification.", "date": "2019-10-23", "date_type": "published", "publication": "Cell Systems", "volume": "9", "number": "4", "publisher": "Cell Press", "pagerange": "321-337", "id_number": "CaltechAUTHORS:20191016-124948167", "issn": "2405-4712", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20191016-124948167", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R01HL119102" }, { "agency": "NIH", "grant_number": "R01HD076915" }, { "agency": "Caltech Beckman Institute" }, { "agency": "Bowes Leadership Chair Fund" }, { "agency": "Louis A. Garfinkle Memorial Laboratory Fund" }, { "agency": "Al Sherman Foundation" }, { "agency": "Albert Billings Ruddock Professorship" } ] }, "doi": "10.1016/j.cels.2019.09.008", "pmcid": "PMC6932747", "primary_object": { "basename": "1-s2.0-S2405471219303163-mmc1.pdf", "url": "https://authors.library.caltech.edu/records/2qmmp-7q537/files/1-s2.0-S2405471219303163-mmc1.pdf" }, "related_objects": [ { "basename": "1-s2.0-S2405471219303163-mmc2.xlsx", "url": "https://authors.library.caltech.edu/records/2qmmp-7q537/files/1-s2.0-S2405471219303163-mmc2.xlsx" }, { "basename": "1-s2.0-S2405471219303163-mmc3.xlsx", "url": "https://authors.library.caltech.edu/records/2qmmp-7q537/files/1-s2.0-S2405471219303163-mmc3.xlsx" }, { "basename": "1-s2.0-S2405471219303163-mmc4.xlsx", "url": "https://authors.library.caltech.edu/records/2qmmp-7q537/files/1-s2.0-S2405471219303163-mmc4.xlsx" }, { "basename": "1-s2.0-S2405471219303163-mmc5.xlsx", "url": "https://authors.library.caltech.edu/records/2qmmp-7q537/files/1-s2.0-S2405471219303163-mmc5.xlsx" }, { "basename": "1-s2.0-S2405471219303163-mmc6.xlsx", "url": "https://authors.library.caltech.edu/records/2qmmp-7q537/files/1-s2.0-S2405471219303163-mmc6.xlsx" }, { "basename": "1-s2.0-S2405471219303163-mmc7.xlsx", "url": "https://authors.library.caltech.edu/records/2qmmp-7q537/files/1-s2.0-S2405471219303163-mmc7.xlsx" }, { "basename": "nihms-1545118.pdf", "url": "https://authors.library.caltech.edu/records/2qmmp-7q537/files/nihms-1545118.pdf" } ], "resource_type": "article", "pub_year": "2019", "author_list": "Zhou, Wen; Yui, Mary A.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/wz591-wkk91", "eprint_id": 89293, "eprint_status": "archive", "datestamp": "2023-08-19 12:56:26", "lastmod": "2023-12-22 23:08:25", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Hosokawa-Hiroyuki", "name": { "family": "Hosokawa", "given": "Hiroyuki" }, "orcid": "0000-0002-9592-2889" }, { "id": "Romero-Wolf-M", "name": { "family": "Romero-Wolf", "given": "Maile" }, "orcid": "0000-0002-8024-7198" }, { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary A." }, "orcid": "0000-0002-3136-2181" }, { "id": "Ungerb\u00e4ck-J", "name": { "family": "Ungerb\u00e4ck", "given": "Jonas" } }, { "id": "Quiloan-M-L-G", "name": { "family": "Quiloan", "given": "Maria L. G." } }, { "id": "Matsumoto-Masaki", "name": { "family": "Matsumoto", "given": "Masaki" } }, { "id": "Nakayama-Keiichi-I", "name": { "family": "Nakayama", "given": "Keiichi I." } }, { "id": "Tanaka-Tomoaki", "name": { "family": "Tanaka", "given": "Tomoaki" }, "orcid": "0000-0002-9761-1750" }, { "id": "Rothenberg-E-V", "name": { "family": "Rothenberg", "given": "Ellen V." }, "orcid": "0000-0002-3901-347X" } ] }, "title": "Bcl11b sets pro-T cell fate by site-specific cofactor recruitment and by repressing Id2 and Zbtb16", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2018 Springer Nature Limited. \n\nReceived 15 March 2018; Accepted 05 September 2018; Published 30 October 2018. \n\nData availability: Additional data that support the findings of this study are available from the corresponding author upon request. In addition to the complete description and explanation of the methods presented here, reagent lists and some general methods are also repeated, along with statistical checklists, in the Nature Research Reporting Summary that accompanies this paper. The GEO accession codes for all the deep-sequencing data reported in this paper are GSE110305, GSE110882 and GSE115744. \n\nWe thank D. Perez, J. Tijerina, and R. Diamond for cell sorting and advice; I. Soto for mouse colony care; V. Kumar for library preparation and sequencing; H. Amrhein and D. Trout for computational assistance; I. Antoshechkin for sequencing management; X.Wang for related exploratory experiments; and members of the Rothenberg group for discussions and reagents. Supported by the Manpei Suzuki Diabetes Foundation (H.H.), the US Public Health Service (R01AI083514 and R01HD076915 to E.V.R.), Grants-in-Aid for Advanced Research and Development Programs for Medical Innovation (T.T.), the Takeda Science Foundation (T.T.), the SENSHINE Medical Research Foundation (T.T.), the Swedish Research Council (J.U.), the California Institute of Regenerative Medicine Bridges to Stem Cell Research Program (Pasadena City College and Caltech; M.R.-W.), the L. A. Garfinkle Memorial Laboratory Fund and the Al Sherman Foundation, special project funds from the Provost and Division of Biology & Biological Engineering of Caltech, and the Albert Billings Ruddock Professorship (E.V.R.). This work was performed in part in the Collaborative Research Project Program of the Medical Institute of Bioregulation, Kyushu University. \n\nAuthor Contributions: H.H. designed the study, performed experiments, analyzed data and wrote the manuscript; M.R.-W. performed experiments, analyzed data and wrote the manuscript; M.A.Y., J.U., M.L.G.Q., M.M., K.I.N., T.T. performed experiments, analyzed data and provided discussions; and E.V.R. designed and supervised the study, analyzed data and wrote the manuscript. \n\nThe authors declare no competing interests.\n\nAccepted Version - nihms-1505977.pdf
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", "abstract": "Multipotent progenitor cells confirm their T cell\u2013lineage identity in the CD4^\u2013CD8^\u2013 double-negative (DN) pro-T cell DN2 stages, when expression of the essential transcription factor Bcl11b begins. In vivo and in vitro stage-specific deletions globally identified Bcl11b-controlled target genes in pro-T cells. Proteomics analysis revealed that Bcl11b associated with multiple cofactors and that its direct action was needed to recruit those cofactors to selective target sites. Regions near functionally regulated target genes showed enrichment for those sites of Bcl11b-dependent recruitment of cofactors, and deletion of individual cofactors relieved the repression of many genes normally repressed by Bcl11b. Runx1 collaborated with Bcl11b most frequently for both activation and repression. In parallel, Bcl11b indirectly regulated a subset of target genes by a gene network circuit via the transcription inhibitor Id2 (encoded by Id2) and transcription factor PLZF (encoded by Zbtb16); Id2 and Zbtb16 were directly repressed by Bcl11b, and Id2 and PLZF controlled distinct alternative programs. Thus, our study defines the molecular basis of direct and indirect Bcl11b actions that promote T cell identity and block alternative potentials.", "date": "2018-12", "date_type": "published", "publication": "Nature Immunology", "volume": "19", "number": "12", "publisher": "Nature Publishing Group", "pagerange": "1427-1440", "id_number": "CaltechAUTHORS:20180830-074139017", "issn": "1529-2908", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20180830-074139017", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Manpei Suzuki Diabetes Foundation" }, { "agency": "NIH", "grant_number": "R01AI083514" }, { "agency": "NIH", "grant_number": "R01HD076915" }, { "agency": "Advanced Research and Development Programs for Medical Innovation" }, { "agency": "Takeda Science Foundation" }, { "agency": "SENSHINE Medical Research Foundation" }, { "agency": "Swedish Research Council" }, { "agency": "California Institute for Regenerative Medicine (CIRM)" }, { "agency": "Louis A. Garfinkle Memorial Laboratory Fund" }, { "agency": "Al Sherman Foundation" }, { "agency": "Caltech Division of Biology and Biological Engineering" }, { "agency": "Albert Billings Ruddock Professorship" } ] }, "doi": "10.1038/s41590-018-0238-4", "pmcid": "PMC6240390", "primary_object": { "basename": "41590_2018_238_Fig9_ESM.jpg", "url": "https://authors.library.caltech.edu/records/wz591-wkk91/files/41590_2018_238_Fig9_ESM.jpg" }, "related_objects": [ { "basename": "41590_2018_238_MOESM9_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/wz591-wkk91/files/41590_2018_238_MOESM9_ESM.xlsx" }, { "basename": "41590_2018_238_MOESM6_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/wz591-wkk91/files/41590_2018_238_MOESM6_ESM.xlsx" }, { "basename": "41590_2018_238_MOESM7_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/wz591-wkk91/files/41590_2018_238_MOESM7_ESM.xlsx" }, { "basename": "41590_2018_238_Fig12_ESM.jpg", "url": "https://authors.library.caltech.edu/records/wz591-wkk91/files/41590_2018_238_Fig12_ESM.jpg" }, { "basename": "41590_2018_238_Fig14_ESM.jpg", "url": "https://authors.library.caltech.edu/records/wz591-wkk91/files/41590_2018_238_Fig14_ESM.jpg" }, { "basename": "41590_2018_238_Fig16_ESM.jpg", "url": "https://authors.library.caltech.edu/records/wz591-wkk91/files/41590_2018_238_Fig16_ESM.jpg" }, { "basename": "41590_2018_238_Fig17_ESM.jpg", "url": "https://authors.library.caltech.edu/records/wz591-wkk91/files/41590_2018_238_Fig17_ESM.jpg" }, { "basename": "41590_2018_238_MOESM2_ESM.pdf", "url": "https://authors.library.caltech.edu/records/wz591-wkk91/files/41590_2018_238_MOESM2_ESM.pdf" }, { "basename": "41590_2018_238_MOESM5_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/wz591-wkk91/files/41590_2018_238_MOESM5_ESM.xlsx" }, { "basename": "41590_2018_238_MOESM8_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/wz591-wkk91/files/41590_2018_238_MOESM8_ESM.xlsx" }, { "basename": "41590_2018_238_MOESM4_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/wz591-wkk91/files/41590_2018_238_MOESM4_ESM.xlsx" }, { "basename": "nihms-1505977.pdf", "url": "https://authors.library.caltech.edu/records/wz591-wkk91/files/nihms-1505977.pdf" }, { "basename": "41590_2018_238_Fig10_ESM.jpg", "url": "https://authors.library.caltech.edu/records/wz591-wkk91/files/41590_2018_238_Fig10_ESM.jpg" }, { "basename": "41590_2018_238_Fig13_ESM.jpg", "url": "https://authors.library.caltech.edu/records/wz591-wkk91/files/41590_2018_238_Fig13_ESM.jpg" }, { "basename": "41590_2018_238_Fig18_ESM.jpg", "url": "https://authors.library.caltech.edu/records/wz591-wkk91/files/41590_2018_238_Fig18_ESM.jpg" }, { "basename": "41590_2018_238_Fig19_ESM.jpg", "url": "https://authors.library.caltech.edu/records/wz591-wkk91/files/41590_2018_238_Fig19_ESM.jpg" }, { "basename": "41590_2018_238_MOESM10_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/wz591-wkk91/files/41590_2018_238_MOESM10_ESM.xlsx" }, { "basename": "41590_2018_238_MOESM3_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/wz591-wkk91/files/41590_2018_238_MOESM3_ESM.xlsx" }, { "basename": "41590_2018_238_Fig11_ESM.jpg", "url": "https://authors.library.caltech.edu/records/wz591-wkk91/files/41590_2018_238_Fig11_ESM.jpg" }, { "basename": "41590_2018_238_Fig15_ESM.jpg", "url": "https://authors.library.caltech.edu/records/wz591-wkk91/files/41590_2018_238_Fig15_ESM.jpg" }, { "basename": "41590_2018_238_Fig8_ESM.jpg", "url": "https://authors.library.caltech.edu/records/wz591-wkk91/files/41590_2018_238_Fig8_ESM.jpg" }, { "basename": "41590_2018_238_MOESM1_ESM.pdf", "url": "https://authors.library.caltech.edu/records/wz591-wkk91/files/41590_2018_238_MOESM1_ESM.pdf" } ], "resource_type": "article", "pub_year": "2018", "author_list": "Hosokawa, Hiroyuki; Romero-Wolf, Maile; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/71hzb-qgg05", "eprint_id": 90521, "eprint_status": "archive", "datestamp": "2023-08-19 12:46:19", "lastmod": "2023-10-23 15:45:00", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Ng-Kenneth-K-N", "name": { "family": "Ng", "given": "Kenneth K. N." } }, { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary A." }, "orcid": "0000-0002-3136-2181" }, { "id": "Mehta-Arnav", "name": { "family": "Mehta", "given": "Arnav" } }, { "id": "Siu-Sharmayne", "name": { "family": "Siu", "given": "Sharmayne" } }, { "id": "Irwin-B", "name": { "family": "Irwin", "given": "Blythe" } }, { "id": "Pease-Shirley-S", "name": { "family": "Pease", "given": "Shirley" } }, { "id": "Hirose-Satoshi", "name": { "family": "Hirose", "given": "Satoshi" } }, { "id": "Elowitz-M-B", "name": { "family": "Elowitz", "given": "Michael B." }, "orcid": "0000-0002-1221-0967" }, { "id": "Rothenberg-E-V", "name": { "family": "Rothenberg", "given": "Ellen V." }, "orcid": "0000-0002-3901-347X" }, { "id": "Kueh-Hao-Yuan", "name": { "family": "Kueh", "given": "Hao Yuan" }, "orcid": "0000-0001-6272-6673" } ] }, "title": "A stochastic epigenetic switch controls the dynamics of T-cell lineage commitment", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2018 Ng et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. \n\nReceived: 26 April 2018; Accepted: 11 October 2018; Published: 20 November 2018. \n\nData availability: Imaging data, along with MATLAB image processing scripts have been deposited in github: https://github.com/KuehLabUW/ictrack/ (copy archived at https://github.com/elifesciences-publications/ictrack). Source data for Figs. 2,3,4,5, Figure 3-figure supplements 1,2 and 3 have also been included. \n\nWe thank M Lerica Gutierrez Quiloan for mouse genotyping and maintenance; N Verduzco and I Soto for animal husbandry; RA Diamond, K Beadle, and D Perez for cell sorting. We also thank members of Kueh, Rothenberg and Elowitz labs for feedback, and T Mitchison for valuable discussions. We also thank Sandy Nandagopal, Pulin Li, Zeba Wunderlich and Nick Pease for comments. This work was funded by an NIH K99/R00 Award (5R00HL119638), a Tietze Foundation Stem Cell Scientist Award, and a CRI/Irvington Postdoctoral Fellowship (to HYK); NIH grants R01AI095943, R01AI083514, and R01HL119102 (to EVR), California Institute for Regenerative Medicine Bridges to Stem Cell Research (to KKHN); and the Louis A Garfinkle Memorial Laboratory Fund, the Al Sherman Foundation, and the Albert Billings Ruddock Professorship (to EVR). \n\nThe funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. \n\nEthics: Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Animals were bred and maintained in either the Laboratory Animal Facility of the California Institute of Technology, or that of the University of Washington. Animal protocols were reviewed and approved by the Institute Animal Care and Use Committees (IACUC) of the California Institute of Technology (Protocols #1445 and #1409) and the University of Washington Protocol #4397-01. \n\nAuthor contributions: Kenneth KH Ng, Data curation, Formal analysis, Investigation, Writing\u2014original draft, Writing\u2014\nreview and editing; Mary A Yui, Data curation, Formal analysis, Investigation; Arnav Mehta, Satoshi Hirose, Investigation; Sharmayne Siu, Blythe Irwin, Formal analysis, Investigation; Shirley Pease, Resources; Michael B Elowitz, Ellen V Rothenberg, Conceptualization, Supervision, Funding acquisition, Methodology, Writing\u2014original draft, Writing\u2014review and editing; Hao Yuan Kueh, Conceptualization, Data curation, Formal analysis, Supervision, Funding acquisition, Investigation, Methodology, Writing\u2014original draft, Writing\u2014review and editing.\n\nPublished - elife-37851-v1.pdf
Submitted - 318675.full.pdf
Supplemental Material - elife-37851-supp1-v1.docx
Supplemental Material - elife-37851-transrepform-v1.docx
", "abstract": "Cell fate decisions occur through the switch-like, irreversible activation of fate-specifying genes. These activation events are often assumed to be tightly coupled to changes in upstream transcription factors, but could also be constrained by cis-epigenetic mechanisms at individual gene loci. Here, we studied the activation of Bcl11b, which controls T-cell fate commitment. To disentangle cis and trans effects, we generated mice where two Bcl11b copies are tagged with distinguishable fluorescent proteins. Quantitative live microscopy of progenitors from these mice revealed that Bcl11b turned on after a stochastic delay averaging multiple days, which varied not only between cells but also between Bcl11b alleles within the same cell. Genetic perturbations, together with mathematical modeling, showed that a distal enhancer controls the rate of epigenetic activation, while a parallel Notch-dependent trans-acting step stimulates expression from activated loci. These results show that developmental fate transitions can be controlled by stochastic cis-acting events on individual loci.", "date": "2018-11-20", "date_type": "published", "publication": "eLife", "volume": "7", "publisher": "eLife Sciences Publications", "pagerange": "Art. No. e37851", "id_number": "CaltechAUTHORS:20181030-143317624", "issn": "2050-084X", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20181030-143317624", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "5R00HL119638" }, { "agency": "Cancer Research Institute" }, { "agency": "NIH", "grant_number": "R01AI095943" }, { "agency": "NIH", "grant_number": "R01AI083514" }, { "agency": "NIH", "grant_number": "R01HL119102" }, { "agency": "California Institute for Regenerative Medicine (CIRM)" }, { "agency": "Louis A. Garfinkle Memorial Laboratory Fund" }, { "agency": "Al Sherman Foundation" }, { "agency": "Albert Billings Ruddock Professorship" }, { "agency": "Howard Hughes Medical Institute (HHMI)" }, { "agency": "John H. Tietze Foundation Trust" } ] }, "doi": "10.7554/eLife.37851", "pmcid": "PMC6245732", "primary_object": { "basename": "elife-37851-transrepform-v1.docx", "url": "https://authors.library.caltech.edu/records/71hzb-qgg05/files/elife-37851-transrepform-v1.docx" }, "related_objects": [ { "basename": "elife-37851-v1.pdf", "url": "https://authors.library.caltech.edu/records/71hzb-qgg05/files/elife-37851-v1.pdf" }, { "basename": "318675.full.pdf", "url": "https://authors.library.caltech.edu/records/71hzb-qgg05/files/318675.full.pdf" }, { "basename": "elife-37851-supp1-v1.docx", "url": "https://authors.library.caltech.edu/records/71hzb-qgg05/files/elife-37851-supp1-v1.docx" } ], "resource_type": "article", "pub_year": "2018", "author_list": "Ng, Kenneth K. N.; Yui, Mary A.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/q3vka-v0232", "eprint_id": 92583, "eprint_status": "archive", "datestamp": "2023-08-19 11:47:04", "lastmod": "2023-10-20 15:53:01", "type": "book_section", "metadata_visibility": "show", "creators": { "items": [ { "id": "Guerrero-Pe\u00f1a-F-A", "name": { "family": "Guerrero-Pe\u00f1a", "given": "Fidel A." } }, { "id": "Marrero-Fernandez-P-D", "name": { "family": "Marrero Fernandez", "given": "Pedro D." } }, { "id": "Ing-Ren-Tsang", "name": { "family": "Ing Ren", "given": "Tsang" } }, { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary" }, "orcid": "0000-0002-3136-2181" }, { "id": "Rothenberg-E-V", "name": { "family": "Rothenberg", "given": "Ellen" }, "orcid": "0000-0002-3901-347X" }, { "id": "Cunha-A", "name": { "family": "Cunha", "given": "Alexandre" }, "orcid": "0000-0002-2541-6024" } ] }, "title": "Multiclass Weighted Loss for Instance Segmentation of Cluttered Cells", "ispublished": "unpub", "full_text_status": "public", "keywords": "Deep learning, instance segmentation, multiclass segmentation, cell segmentation", "note": "\u00a9 2018 IEEE. \n\nWe thank financial support from the Brazilian funding agencies FACEPE, CAPES and CNPq (FAG,PF, TIR), from the Beckman Institute at Caltech to the Center for Advanced Methods in Biological Image Analysis( AC), and thank the IBM Matching Grants Program for computer donation (AC).\n\nSubmitted - 1802.07465.pdf
", "abstract": "We propose a new multiclass weighted loss function for instance segmentation of cluttered cells. We are primarily motivated by the need of developmental biologists to quantify and model the behavior of blood T -cells which might help us in understanding their regulation mechanisms and ultimately help researchers in their quest for developing an effective immunotherapy cancer treatment. Segmenting individual touching cells in cluttered regions is challenging as the feature distribution on shared borders and cell foreground are similar thus difficulting discriminating pixels into proper classes. We present two novel weight maps applied to the weighted cross entropy loss function which take into account both class imbalance and cell geometry. Binary ground truth training data is augmented so the learning model can handle not only foreground and background but also a third touching class. This framework allows training using U - N et. Experiments with our formulations have shown superior results when compared to other similar schemes, outperforming binary class models with significant improvement of boundary adequacy and instance detection. We validate our results on manually annotated microscope images of T-cells.", "date": "2018-10", "date_type": "published", "publisher": "IEEE", "place_of_pub": "Piscataway, NJ", "pagerange": "2451-2455", "id_number": "CaltechAUTHORS:20190201-143229124", "isbn": "9781479970612", "book_title": "2018 25th IEEE International Conference on Image Processing (ICIP)", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20190201-143229124", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Funda\u00e7\u00e3o do Amparo a Ci\u00eancia e Tecnologia (FACEPE)" }, { "agency": "Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior (CAPES)" }, { "agency": "Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico (CNPq)" }, { "agency": "Caltech Beckman Institute" }, { "agency": "IBM" } ] }, "doi": "10.1109/icip.2018.8451187", "primary_object": { "basename": "1802.07465.pdf", "url": "https://authors.library.caltech.edu/records/q3vka-v0232/files/1802.07465.pdf" }, "resource_type": "book_section", "pub_year": "2018", "author_list": "Guerrero-Pe\u00f1a, Fidel A.; Marrero Fernandez, Pedro D.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/pqzdh-spa15", "eprint_id": 89347, "eprint_status": "archive", "datestamp": "2023-08-19 11:10:40", "lastmod": "2023-10-18 22:41:17", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Rodriguez-Rodriguez-S", "name": { "family": "Rodriguez-Rodriguez", "given": "Sonia" } }, { "id": "Wang-Lin", "name": { "family": "Wang", "given": "Lin" } }, { "id": "Zhang-Hujia", "name": { "family": "Zhang", "given": "Hujia" } }, { "id": "Mehrotra-P", "name": { "family": "Mehrotra", "given": "Purvi" }, "orcid": "0000-0001-9369-5013" }, { "id": "Zollman-A", "name": { "family": "Zollman", "given": "Amy" } }, { "id": "Kaplan-Mark", "name": { "family": "Kaplan", "given": "Mark" } }, { "id": "Sandusky-G", "name": { "family": "Sandusky", "given": "George" } }, { "id": "Chiang-Mark", "name": { "family": "Chiang", "given": "Mark" } }, { "id": "Mulloy-J", "name": { "family": "Mulloy", "given": "James" } }, { "id": "Wunderlich-M", "name": { "family": "Wunderlich", "given": "Mark" } }, { "id": "Palmer-J", "name": { "family": "Palmer", "given": "Joycelynne" } }, { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary" }, "orcid": "0000-0002-3136-2181" }, { "id": "Cardoso-A", "name": { "family": "Cardoso", "given": "Angelo" } }, { "id": "Carlesso-N", "name": { "family": "Carlesso", "given": "Nadia" } } ] }, "title": "Loss of the E3 Ubiquitin Ligase SKP2 Limits De Oncogenic Potential of Notch in T-Cell Lymphoblastic Leukemia", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2018 Elsevier B.V. \n\nAvailable online 22 August 2018.", "abstract": "Despite marked clinical successes in the treatment of childhood T-ALL, leukemia relapse, refractory disease and induction failure (around 30% of patients) remain significant clinical problems. New insights in the molecular alterations of ALL have revealed new molecular targets, such as activating mutations of Notch1 (N1), identified in more than 50% of T-ALL patients. However, disruption of N1 signaling by gamma-secretase inhibitors failed to fulfill its clinical promise. Furthermore, little is known about N1 downstream mediators that can be potential therapeutic targets in T-ALL.", "date": "2018-08-22", "date_type": "published", "publication": "Experimental Hematology", "volume": "64", "number": "S1", "publisher": "Elsevier", "pagerange": "S98", "id_number": "CaltechAUTHORS:20180904-084305534", "issn": "0301-472X", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20180904-084305534", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1016/j.exphem.2018.06.133", "resource_type": "article", "pub_year": "2018", "author_list": "Rodriguez-Rodriguez, Sonia; Wang, Lin; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/n0xgs-vjw12", "eprint_id": 67892, "eprint_status": "archive", "datestamp": "2023-08-20 13:04:30", "lastmod": "2023-10-19 22:03:05", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Kueh-Hao-Yuan", "name": { "family": "Kueh", "given": "Hao Yuan" }, "orcid": "0000-0001-6272-6673" }, { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary A." }, "orcid": "0000-0002-3136-2181" }, { "id": "Ng-Kenneth-K-H", "name": { "family": "Ng", "given": "Kenneth K. H." } }, { "id": "Pease-Shirley-S", "name": { "family": "Pease", "given": "Shirley S." } }, { "id": "Zhang-Jingli-A", "name": { "family": "Zhang", "given": "Jingli A." } }, { "id": "Damle-Sagar-S", "name": { "family": "Damle", "given": "Sagar S." } }, { "id": "Freedman-George", "name": { "family": "Freedman", "given": "George" } }, { "id": "Siu-Sharmayne", "name": { "family": "Siu", "given": "Sharmayne" } }, { "id": "Bernstein-Irwin-D", "name": { "family": "Bernstein", "given": "Irwin D." }, "orcid": "0000-0003-0795-3392" }, { "id": "Elowitz-M-B", "name": { "family": "Elowitz", "given": "Michael B." }, "orcid": "0000-0002-1221-0967" }, { "id": "Rothenberg-E-V", "name": { "family": "Rothenberg", "given": "Ellen V." }, "orcid": "0000-0002-3901-347X" } ] }, "title": "Asynchronous combinatorial action of four regulatory factors activates Bcl11b for T cell commitment", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2016 Macmillan Publishers Limited. \n\nReceived 26 January 2016; Accepted 14 June 2016; Published online 04 July 2016. \n\nWe thank M. Lerica Gutierrez Quiloan for assistance with mouse genotyping and maintenance; N. Verduzco and I. Soto for animal husbandry; J. Longmate for help with statistical analysis of alternate-lineage-potential experiments; R.A. Diamond, K. Beadle, J. Grimm, D. Perez and J. Verceles for cell sorting; N. Feng for initial flow cytometric analysis; J. Hahn for advice on BAC recombineering; S. Qin for assistance with qPCR experiments; X.Wang for performing pilot studies with microwell arrays; and J. Ungerb\u00e4ck for assistance with visualizing genome track data. We also thank A. Bhandoola, L. Xu and W. Pear (University of Pennsylvania); J. Telfer (University of Massachusetts) and N. Masuyama (University of Tokyo) for constructs. This work was funded by a CRI/Irvington Postdoctoral Fellowship and a US National Institutes of Health (NIH) K99/R00 Award (K99HL119638A) to H.Y.K.; a California Institute for Regenerative Medicine Bridges to Stem-Cell Research award to K.K.H.N. (TB1-01176); NIH grants to E.V.R. (R01 AI083514, R01 AI095943, RC2 CA148278, R33 HL089123, R01 CA90233 and R01 HL119102) and M.A.Y. (R01 AI064590); NIH/HHS grant U01HL100395 (I.D.B.); the Albert Billings Ruddock Professorship to E.V.R.; and the Al Sherman Foundation and the Louis A. Garfinkle Memorial Laboratory Fund to E.V.R.'s lab. \n\nAuthor Contributions: H.Y.K. designed research, performed experiments, analyzed data and wrote the paper. M.A.Y. designed research, performed experiments, analyzed data and wrote the paper. K.K.H.N., and S.S.P. performed experiments. S.S.D., G.F. and I.D.B. provided reagents. J.A.Z. performed experiments and analyzed data. S.S. analyzed data. M.B.E. designed research. E.V.R. designed research, analyzed data and wrote the paper. \n\nCode availability: Image analysis code is available upon request to H.Y.K. \n\nThe authors declare no competing financial interests.\n\nAccepted Version - nihms795848.pdf
Supplemental Material - ni.3514-S1.pdf
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Supplemental Material - ni_3514-SF8.jpg
", "abstract": "During T cell development, multipotent progenitors relinquish competence for other fates and commit to the T cell lineage by turning on Bcl11b, which encodes a transcription factor. To clarify lineage commitment mechanisms, we followed developing T cells at the single-cell level using Bcl11b knock-in fluorescent reporter mice. Notch signaling and Notch-activated transcription factors collaborate to activate Bcl11b expression irrespectively of Notch-dependent proliferation. These inputs work via three distinct, asynchronous mechanisms: an early locus 'poising' function dependent on TCF-1 and GATA-3, a stochastic-permissivity function dependent on Notch signaling, and a separate amplitude-control function dependent on Runx1, a factor already present in multipotent progenitors. Despite their necessity for Bcl11b expression, these inputs act in a stage-specific manner, providing a multitiered mechanism for developmental gene regulation.", "date": "2016-08", "date_type": "published", "publication": "Nature Immunology", "volume": "17", "number": "8", "publisher": "Nature Publishing Group", "pagerange": "956-965", "id_number": "CaltechAUTHORS:20160613-162442836", "issn": "1529-2908", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20160613-162442836", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "CRI/Irvington Postdoctoral Fellowship" }, { "agency": "NIH", "grant_number": "K99HL119638A" }, { "agency": "California Institute for Regenerative Medicine (CIRM)", "grant_number": "TB1-01176" }, { "agency": "NIH", "grant_number": "R01 AI083514" }, { "agency": "NIH", "grant_number": "R01 AI095943" }, { "agency": "NIH", "grant_number": "RC2 CA148278" }, { "agency": "NIH", "grant_number": "R33 HL089123" }, { "agency": "NIH", "grant_number": "R01 CA90233" }, { "agency": "NIH", "grant_number": "R01 HL119102" }, { "agency": "NIH", "grant_number": "R01 AI064590" }, { "agency": "NIH", "grant_number": "U01HL100395" }, { "agency": "Albert Billings Ruddock Professorship" }, { "agency": "Al Sherman Foundation" }, { "agency": "Louis A. Garfinkle Memorial Laboratory Fund" } ] }, "doi": "10.1038/ni.3514", "pmcid": "PMC4955789", "primary_object": { "basename": "ni.3514-S1.pdf", "url": "https://authors.library.caltech.edu/records/n0xgs-vjw12/files/ni.3514-S1.pdf" }, "related_objects": [ { "basename": "ni_3514-SF3.jpg", "url": "https://authors.library.caltech.edu/records/n0xgs-vjw12/files/ni_3514-SF3.jpg" }, { "basename": "ni_3514-SF6.jpg", "url": "https://authors.library.caltech.edu/records/n0xgs-vjw12/files/ni_3514-SF6.jpg" }, { "basename": "ni_3514-SF7.jpg", "url": "https://authors.library.caltech.edu/records/n0xgs-vjw12/files/ni_3514-SF7.jpg" }, { "basename": "ni_3514-SF8.jpg", "url": "https://authors.library.caltech.edu/records/n0xgs-vjw12/files/ni_3514-SF8.jpg" }, { "basename": "nihms795848.pdf", "url": "https://authors.library.caltech.edu/records/n0xgs-vjw12/files/nihms795848.pdf" }, { "basename": "ni.3514-S2.xlsx", "url": "https://authors.library.caltech.edu/records/n0xgs-vjw12/files/ni.3514-S2.xlsx" }, { "basename": "ni.3514-S3.xlsx", "url": "https://authors.library.caltech.edu/records/n0xgs-vjw12/files/ni.3514-S3.xlsx" }, { "basename": "ni_3514-SF1.jpg", "url": "https://authors.library.caltech.edu/records/n0xgs-vjw12/files/ni_3514-SF1.jpg" }, { "basename": "ni_3514-SF2.jpg", "url": "https://authors.library.caltech.edu/records/n0xgs-vjw12/files/ni_3514-SF2.jpg" }, { "basename": "ni_3514-SF4.jpg", "url": "https://authors.library.caltech.edu/records/n0xgs-vjw12/files/ni_3514-SF4.jpg" }, { "basename": "ni_3514-SF5.jpg", "url": "https://authors.library.caltech.edu/records/n0xgs-vjw12/files/ni_3514-SF5.jpg" } ], "resource_type": "article", "pub_year": "2016", "author_list": "Kueh, Hao Yuan; Yui, Mary A.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/hrf71-wwv17", "eprint_id": 67366, "eprint_status": "archive", "datestamp": "2023-08-20 13:03:38", "lastmod": "2023-10-18 21:07:44", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Ramakrishnan-Parameswaran", "name": { "family": "Ramakrishnan", "given": "Parameswaran" }, "orcid": "0000-0002-1314-827X" }, { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary A." }, "orcid": "0000-0002-3136-2181" }, { "id": "Tomalka-Jeffrey-A", "name": { "family": "Tomalka", "given": "Jeffrey A." } }, { "id": "Majumdar-Devdoot-S", "name": { "family": "Majumdar", "given": "Devdoot" } }, { "id": "Parameswaran-Reshmi", "name": { "family": "Parameswaran", "given": "Reshmi" } }, { "id": "Baltimore-D", "name": { "family": "Baltimore", "given": "David" }, "orcid": "0000-0001-8723-8190" } ] }, "title": "Deficiency of Nuclear Factor-\u03baB c-Rel Accelerates the Development of Autoimmune Diabetes in NOD Mice", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2016 American Diabetes Association. \n\nReceived 24 November 2015 and accepted 15 May 2016. \n\nThe authors thank Hsiou-Chi Liou, Cornell University, for providing c-Rel knockout mice; Diane Mathis and Christophe Benoist, Harvard Medical School, for providing FOXP3-IRES-GFP mice; the California Institute of Technology and Case Western Reserve University animal facilities; Ni Feng, California Institute of Technology, for flow cytometry; and Daniel Kahn and Jevgenij Raskatov, California Institute of Technology, and Timothy Kern, Case Western Reserve University, for insightful discussions. \n\nThis work was initially supported by National Institute of General Medical Sciences grant 2R01-GM-039458 to D.B. and later by Mizutani Foundation for Glycoscience grant 120022, the Clinical and Translational Science Collaborative of Cleveland, grant CTSC UL1-TR-000439 from the National Center for Advancing Translational Sciences, and National Institute of Allergy and Infectious Diseases grant 1R01-AI-116730-01A1 to P.R. M.A.Y. was supported by National Institutes of Health grant AI-64590. J.A.T. was supported by an American Association of Immunologists (AAI) Careers in Immunology Fellowship to P.R. \n\nNo potential conflicts of interest relevant to this article were reported. \n\nAuthor Contributions: P.R. contributed to the study conception and design, data research, and writing of the manuscript. M.A.Y. contributed to the data research, discussion, and editing of the manuscript. J.A.T., D.M., and R.P. contributed to the data research. D.B. contributed to the data interpretation, discussion, and review and editing of the manuscript. P.R. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.\n\nPublished - Ramakrishnan_2016p2367.pdf
Supplemental Material - DB151607SupplementaryData.pdf
", "abstract": "The nuclear factor-\u03baB protein c-Rel plays a critical role in controlling autoimmunity. c-Rel\u2013deficient mice are resistant to streptozotocin-induced diabetes, a drug-induced model of autoimmune diabetes. We generated c-Rel\u2013deficient NOD mice to examine the role of c-Rel in the development of spontaneous autoimmune diabetes. We found that both CD4^+ and CD8^+ T cells from c-Rel\u2013deficient NOD mice showed significantly decreased T-cell receptor\u2013induced IL-2, IFN-\u03b3, and GM-CSF expression. Despite compromised T-cell function, c-Rel deficiency dramatically accelerated insulitis and hyperglycemia in NOD mice along with a substantial reduction in T-regulatory (Treg) cell numbers. Supplementation of isogenic c-Rel\u2013competent Treg cells from prediabetic NOD mice reversed the accelerated diabetes development in c-Rel\u2013deficient NOD mice. The results suggest that c-Rel\u2013dependent Treg cell function is critical in suppressing early-onset autoimmune diabetogenesis in NOD mice. This study provides a novel natural system to study autoimmune diabetes pathogenesis and reveals a previously unknown c-Rel\u2013dependent mechanistic difference between chemically induced and spontaneous diabetogenesis. The study also reveals a unique protective role of c-Rel in autoimmune diabetes, which is distinct from other T-cell\u2013dependent autoimmune diseases such as arthritis and experimental autoimmune encephalomyelitis, where c-Rel promotes autoimmunity.", "date": "2016-08", "date_type": "published", "publication": "Diabetes", "volume": "65", "number": "8", "publisher": "American Diabetes Association", "pagerange": "2367-2379", "id_number": "CaltechAUTHORS:20160525-150035453", "issn": "0012-1797", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20160525-150035453", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "2R01-GM-039458" }, { "agency": "Mizutani Foundation for Glycoscience", "grant_number": "120022" }, { "agency": "Clinical and Translational Science Collaborative of Cleveland" }, { "agency": "NIH", "grant_number": "CTSC UL1-TR-000439" }, { "agency": "NIH", "grant_number": "1R01-AI-116730-01A1" }, { "agency": "NIH", "grant_number": "AI-64590" }, { "agency": "American Association of Immunologists" } ] }, "doi": "10.2337/db15-1607", "pmcid": "PMC4955991", "primary_object": { "basename": "DB151607SupplementaryData.pdf", "url": "https://authors.library.caltech.edu/records/hrf71-wwv17/files/DB151607SupplementaryData.pdf" }, "related_objects": [ { "basename": "Ramakrishnan_2016p2367.pdf", "url": "https://authors.library.caltech.edu/records/hrf71-wwv17/files/Ramakrishnan_2016p2367.pdf" } ], "resource_type": "article", "pub_year": "2016", "author_list": "Ramakrishnan, Parameswaran; Yui, Mary A.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/xv89r-d8958", "eprint_id": 71347, "eprint_status": "archive", "datestamp": "2023-08-20 13:10:14", "lastmod": "2023-10-23 15:39:48", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Rothenberg-E-V", "name": { "family": "Rothenberg", "given": "E." }, "orcid": "0000-0002-3901-347X" }, { "id": "Kueh-Hao-Yuan", "name": { "family": "Kueh", "given": "H. Y." }, "orcid": "0000-0001-6272-6673" }, { "id": "Hosokawa-Hiroyuki", "name": { "family": "Hosokawa", "given": "H." }, "orcid": "0000-0002-9592-2889" }, { "id": "Ng-K-K-H", "name": { "family": "Ng", "given": "K. K. H." } }, { "id": "Mehta-Arnav", "name": { "family": "Mehta", "given": "A." } }, { "id": "Pease-Shirley-S", "name": { "family": "Pease", "given": "S. S." } }, { "id": "Romero-Wolf-M", "name": { "family": "Romero-Wolf", "given": "M." }, "orcid": "0000-0002-8024-7198" }, { "id": "Ungerb\u00e4ck-J", "name": { "family": "Ungerb\u00e4ck", "given": "J." } }, { "id": "Wang-X", "name": { "family": "Wang", "given": "X." } }, { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "M. A." }, "orcid": "0000-0002-3136-2181" }, { "id": "Zeng-W-B", "name": { "family": "Zeng", "given": "W. B." } }, { "id": "Elowitz-M-B", "name": { "family": "Elowitz", "given": "M. B." }, "orcid": "0000-0002-1221-0967" }, { "id": "Mortazavi-A", "name": { "family": "Mortazavi", "given": "A." }, "orcid": "0000-0002-4259-6362" } ] }, "title": "Dissecting the transcriptional regulatory network for early T-cell commitment", "ispublished": "pub", "full_text_status": "restricted", "note": "\u00a9 2016 The Authors. European Journal of Immunology \u00a9 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. \n\nFirst published: 19 August 2016.", "abstract": "Multipotent precursors proliferating in the thymus become committed to a T-cell fate when their access\nto alternative cell fates is intrinsically and unconditionally closed. This process involves very dynamic\nchanges in transcription factor expression and activity: PU.1 and other factors expressed in\nmultipotent progenitors are downregulated and are usually permanently silenced, while T-cell\ntranscription factors, especially Bcl11b, are sharply activated. The abrupt activation of Bcl11b from a\nsilent state is not only a landmark in T-cell differentiation, marking commitment, but also a functional\ncontributor to commitment. Key target genes affected by Bcl11b function at this particular stage will be\ndescribed: many of them appear to be under the control of Bcl11b as a repressor. Recent proteomic\ncharacterization of Bcl11b-containing protein complexes indicates the corepressor and coactivator\npartners that it uses to mediate different types of regulatory activity at different genomic sites. Since\nBcl11b is such a powerful factor, a central question is how the onset of expression of Bcl11b itself is\ncontrolled. The talk will describe the combination of trans-acting factors that are needed to open the\nBcl11b locus and activate it, and show that these factors each play slightly different temporal and\nfunctional roles in the activation process. Interestingly, evidence will also be shown for an epigenetic\ncomponent of Bcl11b regulation that further slows its activation but helps to make it irreversible.", "date": "2016-08", "date_type": "published", "publication": "European Journal of Immunology", "volume": "46", "number": "S1", "publisher": "Wiley", "pagerange": "797", "id_number": "CaltechAUTHORS:20161021-124515838", "issn": "0014-2980", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20161021-124515838", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1002/eji.201670200", "resource_type": "article", "pub_year": "2016", "author_list": "Rothenberg, E.; Kueh, H. Y.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/bfagb-h5k28", "eprint_id": 66465, "eprint_status": "archive", "datestamp": "2023-08-20 11:25:56", "lastmod": "2023-10-18 18:07:16", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Rothenberg-E-V", "name": { "family": "Rothenberg", "given": "Ellen V." }, "orcid": "0000-0002-3901-347X" }, { "id": "Kueh-Hao-Yuan", "name": { "family": "Kueh", "given": "Hao Yuan" }, "orcid": "0000-0001-6272-6673" }, { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary A." }, "orcid": "0000-0002-3136-2181" }, { "id": "Zhang-Jingli-A", "name": { "family": "Zhang", "given": "Jingli A." } } ] }, "title": "Hematopoiesis and T-cell specification as a model developmental system", "ispublished": "pub", "full_text_status": "public", "keywords": "gene regulatory networks, transcription factors, commitment, lineage hierarchy", "note": "\u00a9 2016 John Wiley & Sons. \n\nArticle first published online: 18 APR 2016. \n\nWe gratefully acknowledge the late Eric Davidson for stimulating discussions of developmental gene network properties in diverse systems. We thank past and present members of the Rothenberg and Michael Elowitz groups for valuable advice and sharing of unpublished results, Maria Lerica Gutierrez Quiloan for mouse colony supervision, and Rochelle Diamond, Keith Beadle, and Diana Perez for flow cytometry. The ideas presented here were developed with support by grants from NIH: RC2CA148278, R01AI083514, R01AI095943, R01CA90233, R01HD076915 and R01HL119102 to E. V. R., R01AI064590 to M. A. Y., and K99HL119638A to H. Y. K.; also by the L. A. Garfinkle Memorial Laboratory Fund, and by the Albert Billings Ruddock Professorship to E. V. R. None of the authors has a conflict of interest.\n\nAccepted Version - nihms755561.pdf
", "abstract": "The pathway to generate T cells from hematopoietic stem cells guides progenitors through a succession of fate choices while balancing differentiation progression against proliferation, stage to stage. Many elements of the regulatory system that controls this process are known, but the requirement for multiple, functionally distinct transcription factors needs clarification in terms of gene network architecture. Here, we compare the features of the T-cell specification system with the rule sets underlying two other influential types of gene network models: first, the combinatorial, hierarchical regulatory systems that generate the orderly, synchronized increases in complexity in most invertebrate embryos; second, the dueling 'master regulator' systems that are commonly used to explain bistability in microbial systems and in many fate choices in terminal differentiation. The T-cell specification process shares certain features with each of these prevalent models but differs from both of them in central respects. The T-cell system is highly combinatorial but also highly dose-sensitive in its use of crucial regulatory factors. The roles of these factors are not always T-lineage-specific, but they balance and modulate each other's activities long before any mutually exclusive silencing occurs. T-cell specification may provide a new hybrid model for gene networks in vertebrate developmental systems.", "date": "2016-05", "date_type": "published", "publication": "Immunological Reviews", "volume": "271", "number": "1", "publisher": "Wiley", "pagerange": "72-97", "id_number": "CaltechAUTHORS:20160425-152503200", "issn": "0105-2896", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20160425-152503200", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "RC2CA148278" }, { "agency": "NIH", "grant_number": "R01AI083514" }, { "agency": "NIH", "grant_number": "R01AI095943" }, { "agency": "NIH", "grant_number": "R01CA90233" }, { "agency": "NIH", "grant_number": "R01HD076915" }, { "agency": "NIH", "grant_number": "R01HL119102" }, { "agency": "NIH", "grant_number": "R01AI064590" }, { "agency": "NIH", "grant_number": "K99HL119638A" }, { "agency": "Louis A. Garfinkle Memorial Laboratory Fund" }, { "agency": "Albert Billings Ruddock Professorship" } ] }, "doi": "10.1111/imr.12417", "pmcid": "PMC4837658", "primary_object": { "basename": "nihms755561.pdf", "url": "https://authors.library.caltech.edu/records/bfagb-h5k28/files/nihms755561.pdf" }, "resource_type": "article", "pub_year": "2016", "author_list": "Rothenberg, Ellen V.; Kueh, Hao Yuan; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/5wak3-pk422", "eprint_id": 49215, "eprint_status": "archive", "datestamp": "2023-08-20 02:16:37", "lastmod": "2023-10-17 21:13:25", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary A." }, "orcid": "0000-0002-3136-2181" }, { "id": "Rothenberg-E-V", "name": { "family": "Rothenberg", "given": "Ellen V." }, "orcid": "0000-0002-3901-347X" } ] }, "title": "Developmental gene networks: a triathlon on the course to T cell identity", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2014 Macmillan Publishers Limited.\n\nPublished online 25 July 2014.\n\nThe authors apologize to colleagues whose work helped to\ninspire this Review but could not be cited due to space constraints.\nThe authors thank present and former members of\ntheir group whose published and unpublished data, as well\nas helpful discussion, shaped the ideas presented here. The\nauthors gratefully acknowledge support from the US National\nInstitutes of Health (NIH grant AI064590 to M.A.Y., and\nAI083514, AI095943 and HD076915 to E.V.R.) and the\nAlbert Billings Ruddock Professorship (to E.V.R).\nCompeting interests statement:\nThe authors declare no competing interests.\n\nAccepted Version - nihms620328.pdf
Supplemental Material - nri3702-s1.pdf
Supplemental Material - nri3702-s2.pdf
", "abstract": "Cells acquire their ultimate identities by activating combinations of transcription factors that initiate and sustain expression of the appropriate cell type-specific genes. T cell development depends on the progression of progenitor cells through three major phases, each of which is associated with distinct transcription factor ensembles that control the recruitment of these cells to the thymus, their proliferation, lineage commitment and responsiveness to T cell receptor signals, all before the allocation of cells to particular effector programmes. All three phases are essential for proper T cell development, as are the mechanisms that determine the boundaries between each phase. Cells that fail to shut off one set of regulators before the next gene network phase is activated are predisposed to leukaemic transformation.", "date": "2014-08", "date_type": "published", "publication": "Nature Reviews. Immunology", "volume": "14", "number": "8", "publisher": "Nature Publishing Group", "pagerange": "529-545", "id_number": "CaltechAUTHORS:20140903-154240690", "issn": "1474-1733", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20140903-154240690", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "AI064590" }, { "agency": "NIH", "grant_number": "AI083514" }, { "agency": "NIH", "grant_number": "AI095943" }, { "agency": "NIH", "grant_number": "HD076915" }, { "agency": "Albert Billings Ruddock Professorship" } ] }, "doi": "10.1038/nri3702", "pmcid": "PMC4153685", "primary_object": { "basename": "nihms620328.pdf", "url": "https://authors.library.caltech.edu/records/5wak3-pk422/files/nihms620328.pdf" }, "related_objects": [ { "basename": "nri3702-s1.pdf", "url": "https://authors.library.caltech.edu/records/5wak3-pk422/files/nri3702-s1.pdf" }, { "basename": "nri3702-s2.pdf", "url": "https://authors.library.caltech.edu/records/5wak3-pk422/files/nri3702-s2.pdf" } ], "resource_type": "article", "pub_year": "2014", "author_list": "Yui, Mary A. and Rothenberg, Ellen V." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/vf712-kev80", "eprint_id": 42100, "eprint_status": "archive", "datestamp": "2023-08-19 21:56:44", "lastmod": "2023-10-25 15:38:19", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Rothenberg-E-V", "name": { "family": "Rothenberg", "given": "Ellen V." }, "orcid": "0000-0002-3901-347X" }, { "id": "Champekar-A", "name": { "family": "Champhekar", "given": "Ameya" } }, { "id": "Damle-S-S", "name": { "family": "Damle", "given": "Sagar" } }, { "id": "Del-Real-M-M", "name": { "family": "Del Real", "given": "Marissa Morales" } }, { "id": "Kueh-Hao-Yuan", "name": { "family": "Kueh", "given": "Hao Yuan" }, "orcid": "0000-0001-6272-6673" }, { "id": "Li-Long", "name": { "family": "Li", "given": "Long" } }, { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary A." }, "orcid": "0000-0002-3136-2181" } ] }, "title": "Transcriptional Establishment of Cell-Type Identity: Dynamics and Causal Mechanisms of T-Cell Lineage Commitment", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2013 Cold Spring Harbor Laboratory Press. Published online October 17, 2013 in advance of the print volume. We thank our colleagues Michael Elowitz (Caltech),\nEric Davidson (Caltech), Carsten Peterson (Lund University),\nVijay Chickarmane (Caltech), and Erica Manesso\n(Lund University) for advice and stimulating theoretical\ndiscussions; Marei Dose and Fotini Gounari (University\nof Chicago) for sharing important ChIP-seq data sets;\nIrwin Bernstein (Fred Hutchinson Cancer Research Center)\nfor advice and donating DL1-Fc; Stephen Nutt (Walter\n& Eliza Hall Institute), Mark Leid (Oregon State\nHealth SciencesCenter), and Pentao Liu (Cambridge University)\nfor valuable transgenic mouse strains; and Shirley\nPease and the Caltech Genetically Modified Mouse Service\nfor generation of new fluorescent reporter mouse\nstrains, all of whom contributed to the experiments reviewed\nhere. We are also indebted to Rochelle Diamond\nfor outstanding laboratory management; Robert Butler, Ni\nFeng, Maria Lerica Gutierrez Quiloan, and Edward Hernandez\nfor technical support; Diana Perez, Janice Grimm,\nand Josh Verceles for help with cell sorting; and Ingrid\nSoto for mouse care. Our work was made possible by\nsupport from National Institutes of Health (NIH) grants\nto E.V.R. (RC2 CA148278, R33 HL089123, R01 CA090233, R01 AI083514, and R01 AI095943) and to\nM.A.Y. (R01 AI064590), a Cancer Research Institute-Irvington Fellowship to H.Y.K., the Albert Billings Ruddock\nProfessorship to E.V.R., the Al Sherman Foundation,\nand the Louis A. Garfinkle Memorial Laboratory\nFund.\n\nPublished - Rothenberg_2013p1.pdf
", "abstract": "Precursor cell entry into the T-cell developmental pathway can be divided into two phases by the closure of T-lineage commitment. As cells decide against the last alternative options to the T-cell fate, they turn on the transcription factor Bcl11b and silence expression of a group of multipotent progenitor regulatory factors that include hematopoietic transcription factor PU.1. Functional perturbation tests show that Bcl11b is needed for commitment while PU.1 actively participates in keeping open access to alternative fates, until it is silenced; however, PU.1 and Bcl11b both contribute positively to T-cell development. Our recent work reviewed here sheds light on the transcriptional regulatory network that determines the timing and irreversibility of Bcl11b activation, the ways that Notch signaling from the thymic microenvironment restricts the action of PU.1 to prevent it from diverting cells to non-T fates, and the target genes that PU.1 still regulates under the influence of Notch signaling to contribute to T-cell generation. We argue that T-cell development depends on the sequential operation of two interlaced, but mutually antagonistic, gene regulatory networks, one initially supporting expansion before commitment and the other imposing a \"terminal\" differentiation process on committed cells.", "date": "2013-10-17", "date_type": "published", "publication": "Cold Spring Harbor Symposia on Quantitative Biology", "volume": "78", "publisher": "Cold Spring Harbor Laboratory", "pagerange": "1-11", "id_number": "CaltechAUTHORS:20131028-142315690", "issn": "0091-7451", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20131028-142315690", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "RC2 CA148278" }, { "agency": "NIH", "grant_number": "R33 HL089123" }, { "agency": "NIH", "grant_number": "R01 CA090233" }, { "agency": "NIH", "grant_number": "R01 AI083514" }, { "agency": "NIH", "grant_number": "R01 AI095943" }, { "agency": "NIH", "grant_number": "R01 AI064590" }, { "agency": "Cancer Research Institute-Irvington Fellowship" }, { "agency": "Albert Billings Ruddock Professorship" }, { "agency": "Al Sherman Foundation" }, { "agency": "Louis A. Garfinkle Memorial Laboratory Fund" } ] }, "doi": "10.1101/sqb.2013.78.020271", "pmcid": "PMC3990665", "primary_object": { "basename": "Rothenberg_2013p1.pdf", "url": "https://authors.library.caltech.edu/records/vf712-kev80/files/Rothenberg_2013p1.pdf" }, "resource_type": "article", "pub_year": "2013", "author_list": "Rothenberg, Ellen V.; Champhekar, Ameya; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/1a6m8-c2314", "eprint_id": 38294, "eprint_status": "archive", "datestamp": "2023-08-19 19:28:24", "lastmod": "2023-10-23 20:01:20", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary A." }, "orcid": "0000-0002-3136-2181" }, { "id": "Feng-Ni", "name": { "family": "Feng", "given": "Ni" } }, { "id": "Zhang-Jingli-A", "name": { "family": "Zhang", "given": "Jingli A." } }, { "id": "Liaw-Chen-Yee", "name": { "family": "Liaw", "given": "Chen Yee" } }, { "id": "Rothenberg-E-V", "name": { "family": "Rothenberg", "given": "Ellen V." }, "orcid": "0000-0002-3901-347X" }, { "id": "Longmate-J-A", "name": { "family": "Longmate", "given": "Jeffrey A." } } ] }, "title": "Loss of T Cell Progenitor Checkpoint Control Underlies Leukemia Initiation in Rag1-Deficient Nonobese Diabetic Mice", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2013 by The American Association of Immunologists, Inc. \n\nReceived October 31, 2012. Accepted January 21, 2013. \nPublished online before print February 25, 2013. \n\nThis work was supported by National Institutes of Health Grant AI64590 (to M.A.Y.); California Institute of Technology Summer Undergraduate Research Fellowships (to C.Y.L.); the Albert Billings Ruddock Professorship (to E.V.R.); the Louis A. Garfinkle Memorial Laboratory Fund; and the Al Sherman Foundation. \n\nWe thank Brian Williams, Justine Chia, Avni Gandhi, and Sagar Damle (California Institute of Technology) for technical and bioinformatics assistance; Donna Walls and Weidong Zhang (The Jackson Laboratory) for genotyping and preliminary statistical analysis; J.C. Zu\u00f1iga-Pfl\u00fccker (University of Toronto) for providing OP9-DL1 and OP9-DL4 cells; L.S. Wicker (Cambridge University) for NOD.B10Idd9 congenic mice; Rochelle Diamond, Diane Perez, and Pat Koen from the California Institute of Technology Flow Cytometry and Cell Sorting Facility; Scott Washburn and Natasha Bouey for animal care; and Ali Mortazavi and members of the Rothenberg Laboratory for helpful suggestions. The authors have no financial conflicts of interest.\n\nAccepted Version - nihms439439.pdf
", "abstract": "NOD mice exhibit major defects in the earliest stages of T cell development in the thymus. Genome-wide genetic and transcriptome analyses were used to investigate the origins and consequences of an early T cell developmental checkpoint breakthrough in Rag1-deficient NOD mice. Quantitative trait locus analysis mapped the presence of checkpoint breakthrough cells to several known NOD diabetes susceptibility regions, particularly insulin-dependent diabetes susceptibility genes (Idd)9/11 on chromosome 4, suggesting common genetic origins for T cell defects affecting this trait and autoimmunity. Genome-wide RNA deep-sequencing of NOD and B6 Rag1-deficient thymocytes revealed the effects of genetic background prior to breakthrough, as well as the cellular consequences of the breakthrough. Transcriptome comparison between the two strains showed enrichment in differentially expressed signal transduction genes, prominently tyrosine kinase and actin-binding genes, in accord with their divergent sensitivities to activating signals. Emerging NOD breakthrough cells aberrantly expressed both stem cell\u2013associated proto-oncogenes, such as Lmo2, Hhex, Lyl1, and Kit, which are normally repressed at the commitment checkpoint, and post\u2013\u03b2-selection checkpoint genes, including Cd2 and Cd5. Coexpression of genes characteristic of multipotent progenitors and more mature T cells persists in the expanding population of thymocytes and in the thymic leukemias that emerge with age in these mice. These results show that Rag1-deficient NOD thymocytes have T cell defects that can collapse regulatory boundaries at two early T cell checkpoints, which may predispose them to both leukemia and autoimmunity.", "date": "2013-04-01", "date_type": "published", "publication": "Journal of Immunology", "volume": "190", "number": "7", "publisher": "American Association of Immunologists", "pagerange": "3276-3288", "id_number": "CaltechAUTHORS:20130506-110729222", "issn": "0022-1767", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130506-110729222", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "AI64590" }, { "agency": "Caltech Summer Undergraduate Research Fellowship (SURF)" }, { "agency": "Albert Billings Ruddock Professorship" }, { "agency": "Louis A. Garfinkle Memorial Laboratory Fund" }, { "agency": "Al Sherman Foundation" } ] }, "doi": "10.4049/jimmunol.1202970", "pmcid": "PMC3608698", "primary_object": { "basename": "nihms439439.pdf", "url": "https://authors.library.caltech.edu/records/1a6m8-c2314/files/nihms439439.pdf" }, "resource_type": "article", "pub_year": "2013", "author_list": "Yui, Mary A.; Feng, Ni; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/bk0ar-jry12", "eprint_id": 22925, "eprint_status": "archive", "datestamp": "2023-08-19 05:17:15", "lastmod": "2023-10-23 17:21:13", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Feng-Ni", "name": { "family": "Feng", "given": "Ni" } }, { "id": "Vegh-P", "name": { "family": "Vegh", "given": "Patricia" } }, { "id": "Rothenberg-E-V", "name": { "family": "Rothenberg", "given": "Ellen V." }, "orcid": "0000-0002-3901-347X" }, { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary A." }, "orcid": "0000-0002-3136-2181" } ] }, "title": "Lineage Divergence at the First TCR-Dependent Checkpoint: Preferential \u03b3\u03b4 and Impaired \u03b1\u03b2 T Cell Development in Nonobese Diabetic Mice", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2011 American Association of Immunologists. \n\nReceived for publication August 2, 2010. Accepted for publication November 9, 2010. \n\nWe thank J. C. Zu\u00f1iga-Pfl\u00fccker for generously providing OP9-DL1 and OP9-DL4 cells for these experiments, Rochelle Diamond, Stephanie Adams, Diane Perez, and Pat Koen from the Caltech Cell Sorting Facility for cell sorting, Natasha Bouey, Robert Butler, Ruben Bayon, and Beth Olsen for excellent animal care, Marion Duprilot for preliminary gene expression data, and Tom Taghon (University of Ghent, Belgium) and members of the Rothenberg laboratory, especially Rochelle Diamond, for helpful suggestions. This work was supported by grants from the Juvenile Diabetes Research Foundation International, the National Institutes of Health (AI64590 to M.A.Y.), the Al Sherman Foundation, the Louis A. Garfinkle Memorial Laboratory Fund, the Vanguard Charitable Endowment for Diabetes in Memory of Bently Pritsker, and the Albert Billings Ruddock Professorship (to E.V.R.).\n\nAccepted Version - nihms-596890.pdf
", "abstract": "The first TCR-dependent checkpoint in the thymus determines \u03b1\u03b2 versus \u03b3\u03b4 T lineage fate and sets the stage for later T cell differentiation decisions. We had previously shown that early T cells in NOD mice that are unable to rearrange a TCR exhibit a defect in checkpoint enforcement at this stage. To determine if T cell progenitors from wild-type NOD mice also exhibit cellautonomous defects in development, we investigated their differentiation in the Notch-ligand\u2013presenting OP9-DL1 coculture system, as well as by analysis of T cell development in vivo. Cultured CD4 and CD8 double-negative cells from NOD mice exhibited major defects in the generation of CD4 and CD8 double-positive \u03b1\u03b2 T cells, whereas \u03b3\u03b4 T cell development from bipotent precursors was enhanced. Limiting dilution and single-cell experiments show that the divergent effects on \u03b1\u03b2 and \u03b3\u03b4\nT cell development did not spring from biased lineage choice but from increased proliferation of \u03b3\u03b4 T cells and impaired accumulation of \u03b1\u03b2 T lineage double-positive cells. In vivo, NOD early T cell subsets in the thymus also show characteristics indicative of defective \u03b2-selection, and peripheral \u03b1\u03b2 T cells are poorly established in mixed bone marrow chimeras, contrasting with strong \u03b3\u03b4 T as well as B cell repopulation. Thus, NOD T cell precursors reveal divergent, lineage-specific differentiation abnormalities in vitro and in vivo from the first TCR-dependent developmental choice point, which may have consequences for\nsubsequent lineage decisions and effector functions.", "date": "2011-01-15", "date_type": "published", "publication": "Journal of Immunology", "volume": "186", "number": "2", "publisher": "American Association of Immunologists", "pagerange": "826-837", "id_number": "CaltechAUTHORS:20110316-093514596", "issn": "0022-1767", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20110316-093514596", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Juvenile Diabetes Research Foundation International" }, { "agency": "NIH", "grant_number": "AI64590" }, { "agency": "Al Sherman Foundation" }, { "agency": "Louis A. Garfinkle Memorial Laboratory Fund" }, { "agency": "Vanguard Charitable Endowment for Diabetes" }, { "agency": "Albert Billings Ruddock Professorship" } ] }, "doi": "10.4049/jimmunol.1002630", "pmcid": "PMC4087166", "primary_object": { "basename": "nihms-596890.pdf", "url": "https://authors.library.caltech.edu/records/bk0ar-jry12/files/nihms-596890.pdf" }, "resource_type": "article", "pub_year": "2011", "author_list": "Feng, Ni; Vegh, Patricia; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/avw6p-a8s32", "eprint_id": 18867, "eprint_status": "archive", "datestamp": "2023-08-19 02:49:17", "lastmod": "2023-10-20 19:08:34", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary A." }, "orcid": "0000-0002-3136-2181" }, { "id": "Feng-Ni", "name": { "family": "Feng", "given": "Ni" } }, { "id": "Rothenberg-E-V", "name": { "family": "Rothenberg", "given": "Ellen V." }, "orcid": "0000-0002-3901-347X" } ] }, "title": "Fine-Scale Staging of T Cell Lineage Commitment in Adult Mouse Thymus", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2010 by The American Association of Immunologists, Inc. \n\nReceived for publication February 26, 2010. Accepted for publication April 25, 2010. \n\nThis work was supported by National Institutes of Health Grant R01 AI064590 (to M.A.Y.), the Louis A. Garfinkle Memorial Laboratory Fund, the Al Sherman Foundation, and the Albert Billings Ruddock Professorship (to E.V.R.).\n\nAccepted Version - nihms596886.pdf
", "abstract": "T cell development is marked by the loss of alternative lineage choices accompanying specification and commitment to the T cell lineage. Commitment occurs between the CD4 and CD8 double-negative (DN) 2 and DN3 stages in mouse early T cells. To determine the gene regulatory changes that accompany commitment, we sought to distinguish and characterize the earliest committed wild-type DN adult thymocytes. A transitional cell population, defined by the first downregulation of surface c-Kit expression, was found to have lost the ability to differentiate into dendritic cells and NK cells when cultured without Notch-Delta signals. In the presence of Notch signaling, this subset generates T lineage descendants in an ordered precursor\u2013product relationship between DN2, with the highest levels of surface c-Kit, and c-Kit\u2013low DN3 cells. These earliest committed cells show only a few differences in regulatory gene expression, compared with uncommitted DN2 cells. They have not yet established the full expression of Notch-related and T cell differentiation genes characteristic of DN3 cells before \u03b2 selection. Instead, the downregulation of select stem cell and non-T lineage genes appears to be key to the extinction of alternative lineage choices.", "date": "2010-06-11", "date_type": "published", "publication": "Journal of Immunology", "volume": "185", "number": "1", "publisher": "American Association of Immunologists", "pagerange": "284-293", "id_number": "CaltechAUTHORS:20100630-085544779", "issn": "0022-1767", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20100630-085544779", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R01 AI064590" }, { "agency": "Louis A. Garfinkle Memorial Laboratory Fund" }, { "agency": "Al Sherman Foundation" }, { "agency": "Albert Billings Ruddock Professorship" } ] }, "doi": "10.4049/jimmunol.1000679", "pmcid": "PMC4091773", "primary_object": { "basename": "nihms596886.pdf", "url": "https://authors.library.caltech.edu/records/avw6p-a8s32/files/nihms596886.pdf" }, "resource_type": "article", "pub_year": "2010", "author_list": "Yui, Mary A.; Feng, Ni; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/v3q97-9pr23", "eprint_id": 14516, "eprint_status": "archive", "datestamp": "2023-08-22 14:14:06", "lastmod": "2023-10-18 18:04:15", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "David-Fung-E-S", "name": { "family": "David-Fung", "given": "Elizabeth-Sharon" } }, { "id": "Butler-R", "name": { "family": "Butler", "given": "Robert" } }, { "id": "Buzi-G", "name": { "family": "Buzi", "given": "Gentian" }, "orcid": "0000-0002-8724-3405" }, { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary A." }, "orcid": "0000-0002-3136-2181" }, { "id": "Diamond-R-A", "name": { "family": "Diamond", "given": "Rochelle A." } }, { "id": "Anderson-M-K", "name": { "family": "Anderson", "given": "Michele K." } }, { "id": "Rowen-L", "name": { "family": "Rowen", "given": "Lee" } }, { "id": "Rothenberg-E-V", "name": { "family": "Rothenberg", "given": "Ellen V." }, "orcid": "0000-0002-3901-347X" } ] }, "title": "Transcription factor expression dynamics of early T-lymphocyte specification and commitment", "ispublished": "pub", "full_text_status": "public", "keywords": "T-cell development; Notch; Thymus; Lineage commitment; Hematopoiesis", "note": "\u00a9 2009 Elsevier. \n\nReceived 16 September 2008; accepted 17 October 2008. Available online 5 November 2008. \n\nWe are deeply indebted to Dr. Howard Petrie (Scripps Florida) for valuable discussions during the gestation of this work and for generous sharing of data prior to publication. We are also grateful to Dr. Hamid Bolouri (Caltech and Institute for Systems Biology) and Dr. Eric Davidson (Caltech) for insightful critiques, encouragement, and advice. We also thank Brian Birditt and Scott Bloom (Institute for Systems Biology) for their excellent work sequencing and identifying the cDNA clones from our gene discovery; Marissa Morales and Dr. Rashmi Pant, for key contributions to the gene expression measurements and their validation; Dr. Tom Taghon, for generous collaboration on making the samples for the OP9 experiments; Gillian Giorgio, for early help curating the sequence files; Stephanie Adams of the Caltech Flow Cytometry Facility, for outstanding help with the sorting; and Robin Condie and Ruben Bayon for excellent care of the animals. \n\nThis work was undertaken with support from the Stowers Institute for Medical Research and then supported by grants from the NSF (MCB9983129) and the NIH (R01 CA90233 and R33 HL089123), and by the Louis A. Garfinkle Memorial Laboratory Fund, the Al Sherman Fund, the Albert Billings Ruddock Professorship, and the DNA Sequencer Royalty Fund at Caltech.\n\nAccepted Version - nihms92196.pdf
Supplemental Material - DAVdb09supp.doc
Supplemental Material - DAVdb09tableS1.doc
", "abstract": "Mammalian T lymphocytes are a prototype for development from adult pluripotent stem cells. While T-cell specification is driven by Notch signaling, T-lineage commitment is only finalized after prolonged Notch activation. However, no T-lineage specific regulatory factor has been reported that mediates commitment. We used a gene-discovery approach to identify additional candidate T-lineage transcription factors and characterized expression of > 100 regulatory genes in early T-cell precursors using realtime RT-PCR. These regulatory genes were also monitored in multilineage precursors as they entered T-cell or non-T-cell pathways in vitro; in non-T cells ex vivo; and in later T-cell developmental stages after lineage commitment. At least three major expression patterns were observed. Transcription factors in the largest group are expressed at relatively stable levels throughout T-lineage specification as a legacy from prethymic precursors, with some continuing while others are downregulated after commitment. Another group is highly expressed in the earliest stages only, and is downregulated before or during commitment. Genes in a third group undergo upregulation at one of three distinct transitions, suggesting a positive regulatory cascade. However, the transcription factors induced during commitment are not T-lineage specific. Different members of the same transcription factor family can follow opposite trajectories during specification and commitment, while factors co-expressed early can be expressed in divergent patterns in later T-cell development. Some factors reveal new regulatory distinctions between \u03b1\u03b2 and \u03b3\u03b4 T-lineage differentiation. These results show that T-cell identity has an essentially complex regulatory basis and provide a detailed framework for regulatory network modeling of T-cell specification.", "date": "2009-01-15", "date_type": "published", "publication": "Developmental Biology", "volume": "325", "number": "2", "publisher": "Elsevier", "pagerange": "444-467", "id_number": "CaltechAUTHORS:20090708-093942975", "issn": "0012-1606", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20090708-093942975", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Stowers Institute for Medical Research" }, { "agency": "NSF", "grant_number": "MCB9983129" }, { "agency": "NIH", "grant_number": "R01 CA90233" }, { "agency": "NIH", "grant_number": "R33 HL089123" }, { "agency": "Louis A. Garfinkle Memorial Laboratory Fund" }, { "agency": "Al Sherman Fund" }, { "agency": "Albert Billings Ruddock Professorship" }, { "agency": "DNA Sequencer Royalty Fund, Caltech" } ] }, "doi": "10.1016/j.ydbio.2008.10.021", "pmcid": "PMC2663971", "primary_object": { "basename": "DAVdb09supp.doc", "url": "https://authors.library.caltech.edu/records/v3q97-9pr23/files/DAVdb09supp.doc" }, "related_objects": [ { "basename": "DAVdb09tableS1.doc", "url": "https://authors.library.caltech.edu/records/v3q97-9pr23/files/DAVdb09tableS1.doc" }, { "basename": "nihms92196.pdf", "url": "https://authors.library.caltech.edu/records/v3q97-9pr23/files/nihms92196.pdf" } ], "resource_type": "article", "pub_year": "2009", "author_list": "David-Fung, Elizabeth-Sharon; Butler, Robert; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/7vqdh-5e689", "eprint_id": 13019, "eprint_status": "archive", "datestamp": "2023-08-22 13:55:35", "lastmod": "2023-10-17 21:42:55", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Georgescu-C", "name": { "family": "Georgescu", "given": "Constantin" } }, { "id": "Longabaugh-W-J-R", "name": { "family": "Longabaugh", "given": "William J. R." } }, { "id": "Scripture-Adams-D-D", "name": { "family": "Scripture-Adams", "given": "Dierdre D." } }, { "id": "David-Fung-E-S", "name": { "family": "David-Fung", "given": "Elizabeth-Sharon" } }, { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary A." }, "orcid": "0000-0002-3136-2181" }, { "id": "Zarnegar-M-A", "name": { "family": "Zarnegar", "given": "Mark A." } }, { "id": "Bolouri-H", "name": { "family": "Bolouri", "given": "Hamid" } }, { "id": "Rothenberg-E-V", "name": { "family": "Rothenberg", "given": "Ellen V." }, "orcid": "0000-0002-3901-347X" } ] }, "title": "A gene regulatory network armature for T lymphocyte specification", "ispublished": "pub", "full_text_status": "public", "keywords": "GATA-3; Notch; PU.1; T cell development; transcriptional regulation", "note": "\u00a9 2008 The National Academy of Sciences of the USA. \n\nEdited by Michael S. Levine, University of California, Berkeley, CA, and approved September 8, 2008 (received for review July 6, 2008). This article is a PNAS Direct Submission. Published online before print December 22, 2008, doi: 10.1073/pnas.0806501105 \n\nWe thank Dr. Howard Petrie (Scripps Florida, Jupiter) for valuable discussions and sharing unpublished data for comparison with ours and Robert Butler, Ni Feng, and Koorosh J. Elihu for excellent technical help. This work was supported by National Institutes of Health Grants R33 HL089102 (to H.B.) and R33 HL089123 (to E.V.R.), using data from work supported by National Institutes of Health Grants CA90233, CA98925, DK73658, and AI064590 (to M.A.Y.), the Albert Billings Ruddock Professorship, the Louis A. Garfinkle Memorial Laboratory Fund, the Al Sherman Fund, and the DNA Sequencer Royalty Fund. \n\nThis paper results from the Arthur M. Sackler Colloquium of the National Academy of Sciences, \"Gene Networks in Animal Development and Evolution,\" held February 15\u201316, 2008, at the Arnold and Mabel Beckman Center of the National Academies of Sciences and Engineering in Irvine, CA. The complete program and audio files of most presentations are available on the NAS web site at: http://www.nasonline.org/SACKLER_Gene_Networks. \n\nAuthor contributions: H.B. and E.V.R. designed research; D.D.S.-A., E.-S.D.-F., M.A.Y., and M.A.Z. performed research; C.G., W.J.R.L., and H.B. contributed new reagents/analytic tools; C.G., W.J.R.L., D.D.S.-A., E.-S.D.-F., M.A.Y., M.A.Z., H.B., and E.V.R. analyzed data; and C.G., H.B., and E.V.R. wrote the paper. \n\nThe authors declare no conflict of interest. \n\nThis article contains supporting information online at www.pnas.org/cgi/content/full/0806501105/DCSupplemental.\n\nPublished - GEOpnas08.pdf
Supplemental Material - GEOpnas08supp.pdf
", "abstract": "Choice of a T lymphoid fate by hematopoietic progenitor cells depends on sustained Notch\u2013Delta signaling combined with tightly regulated activities of multiple transcription factors. To dissect the regulatory network connections that mediate this process, we have used high-resolution analysis of regulatory gene expression trajectories from the beginning to the end of specification, tests of the short-term Notch dependence of these gene expression changes, and analyses of the effects of overexpression of two essential transcription factors, namely PU.1 and GATA-3. Quantitative expression measurements of >50 transcription factor and marker genes have been used to derive the principal components of regulatory change through which T cell precursors progress from primitive multipotency to T lineage commitment. Our analyses reveal separate contributions of Notch signaling, GATA-3 activity, and down-regulation of PU.1. Using BioTapestry (www.BioTapestry.org), the results have been assembled into a draft gene regulatory network for the specification of T cell precursors and the choice of T as opposed to myeloid/dendritic or mast-cell fates. This network also accommodates effects of E proteins and mutual repression circuits of Gfi1 against Egr-2 and of TCF-1 against PU.1 as proposed elsewhere, but requires additional functions that remain unidentified. Distinctive features of this network structure include the intense dose dependence of GATA-3 effects, the gene-specific modulation of PU.1 activity based on Notch activity, the lack of direct opposition between PU.1 and GATA-3, and the need for a distinct, late-acting repressive function or functions to extinguish stem and progenitor-derived regulatory gene expression.", "date": "2008-12-23", "date_type": "published", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "volume": "105", "number": "51", "publisher": "National Academy of Sciences", "pagerange": "20100-20105", "id_number": "CaltechAUTHORS:GEOpnas08", "issn": "0027-8424", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:GEOpnas08", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R33 HL089102" }, { "agency": "NIH", "grant_number": "R33 HL089123" }, { "agency": "NIH", "grant_number": "CA90233" }, { "agency": "NIH", "grant_number": "CA98925" }, { "agency": "NIH", "grant_number": "DK73658" }, { "agency": "NIH", "grant_number": "AI064590" }, { "agency": "Albert Billings Ruddock Professorship" }, { "agency": "Louis A. Garfinkle Memorial Laboratory Fund" }, { "agency": "Al Sherman Foundation" }, { "agency": "DNA Sequencer Royalty Fund, Caltech" } ] }, "doi": "10.1073/pnas.0806501105", "pmcid": "PMC2629331", "primary_object": { "basename": "GEOpnas08supp.pdf", "url": "https://authors.library.caltech.edu/records/7vqdh-5e689/files/GEOpnas08supp.pdf" }, "related_objects": [ { "basename": "GEOpnas08.pdf", "url": "https://authors.library.caltech.edu/records/7vqdh-5e689/files/GEOpnas08.pdf" } ], "resource_type": "article", "pub_year": "2008", "author_list": "Georgescu, Constantin; Longabaugh, William J. R.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/98jxk-s1531", "eprint_id": 55889, "eprint_status": "archive", "datestamp": "2023-08-19 21:56:42", "lastmod": "2023-10-20 23:22:35", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Rothenberg-E-V", "name": { "family": "Rothenberg", "given": "Ellen V." }, "orcid": "0000-0002-3901-347X" }, { "id": "Moore-J-E", "name": { "family": "Moore", "given": "Jonathan E." } }, { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary A." }, "orcid": "0000-0002-3136-2181" } ] }, "title": "Launching the T-cell-lineage developmental programme", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2008 Nature Publishing Group.\n\nThe authors wish to thank T. Graf, H. Kawamoto, B. Kee, C. Murre, H. Petrie and N. Speck for valuable discussions and generous sharing of unpublished results. We apologize to many authors whose work we could not adequately cite. We also thank members of the Rothenberg group for collegial interchange, advice and permission to cite unpublished work, and N. Feng, R. Butler and D. Perez for technical support. The authors were supported by grants from the National Institutes of Health (NIH), USA, to E.V.R. (R01 CA90233 and R01 CA98925), M.A.Y. (R01 AI064590) and J.E.M. (F32 AI068366). E.V.R. gratefully acknowledges\nthe Albert Billings Ruddock Professorship.\n\nAccepted Version - nihms305535.pdf
", "abstract": "Multipotent blood progenitor cells enter the thymus and begin a protracted differentiation process in which they gradually acquire T-cell characteristics while shedding their legacy of developmental plasticity. Notch signalling and basic helix-loop-helix E-protein transcription factors collaborate repeatedly to trigger and sustain this process throughout the period leading up to T-cell lineage commitment. Nevertheless, the process is discontinuous with separately regulated steps that demand roles for additional collaborating factors. This Review discusses new evidence on the coordination of specification and commitment in the early T-cell pathway; effects of microenvironmental signals; the inheritance of stem-cell regulatory factors; and the ensemble of transcription factors that modulate the effects of Notch and E proteins, to distinguish individual stages and to polarize T-cell-lineage fate determination.", "date": "2008-01", "date_type": "published", "publication": "Nature Reviews. Immunology", "volume": "8", "number": "1", "publisher": "Nature Publishing Group", "pagerange": "9-21", "id_number": "CaltechAUTHORS:20150318-105708662", "issn": "1474-1733", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20150318-105708662", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R01 CA90233" }, { "agency": "NIH", "grant_number": "R01 CA98925" }, { "agency": "NIH", "grant_number": "R01 AI064590" }, { "agency": "NIH Postdoctoral Fellowship", "grant_number": "F32 AI068366" }, { "agency": "Albert Billings Ruddock Professorship" } ] }, "doi": "10.1038/nri2232", "pmcid": "PMC3131407", "primary_object": { "basename": "nihms305535.pdf", "url": "https://authors.library.caltech.edu/records/98jxk-s1531/files/nihms305535.pdf" }, "resource_type": "article", "pub_year": "2008", "author_list": "Rothenberg, Ellen V.; Moore, Jonathan E.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/t7vnq-5vs43", "eprint_id": 74700, "eprint_status": "archive", "datestamp": "2023-08-19 21:53:02", "lastmod": "2023-10-24 22:52:00", "type": "book_section", "metadata_visibility": "show", "creators": { "items": [ { "id": "Rothenberg-E-V", "name": { "family": "Rothenberg", "given": "Ellen V." }, "orcid": "0000-0002-3901-347X" }, { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary A." }, "orcid": "0000-0002-3136-2181" } ] }, "title": "Development of T cells", "ispublished": "unpub", "full_text_status": "public", "abstract": "[no abstract]", "date": "2008", "date_type": "published", "publisher": "Lippincott Williams & Wilkins", "place_of_pub": "Philadelphia, PA", "pagerange": "376-406", "id_number": "CaltechAUTHORS:20170303-120032163", "isbn": "9780781765190", "book_title": "Fundamental Immunology, Sixth Edition", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170303-120032163", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "contributors": { "items": [ { "id": "Paul-W-E", "name": { "family": "Paul", "given": "William E." } } ] }, "resource_type": "book_section", "pub_year": "2008", "author_list": "Rothenberg, Ellen V. and Yui, Mary A." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/40nhk-d5430", "eprint_id": 55856, "eprint_status": "archive", "datestamp": "2023-08-19 20:41:49", "lastmod": "2023-10-20 23:18:38", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Taghon-T", "name": { "family": "Taghon", "given": "Tom" } }, { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary A." }, "orcid": "0000-0002-3136-2181" }, { "id": "Rothenberg-E-V", "name": { "family": "Rothenberg", "given": "Ellen V." }, "orcid": "0000-0002-3901-347X" } ] }, "title": "Mast cell lineage diversion of T lineage precursors by the essential T cell transcription factor GATA-3", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2007 Nature Publishing Group.\n\nReceived 17 April; accepted 11 June; published online 1 July 2007.\n\nWe thank S.L. Adams and D. Perez for assistance in cell sorting; A. Arias for\ngenerating early results related to this project; M.K. Anderson, C.C. Tydell and\nE.-S. David-Fung for primers; R. Diamond for cell separation advice and help\nwith sorting; R. Bayon, N. Bouey and L. del Carmen Sandoval for animal care;\nP. Koen for cytometry support; R. Butler, N. Feng and G. De Smet for technical\nassistance; and V. Stove and colleagues (Department of Clinical Chemistry,\nUniversity of Ghent) and K. Swerts (Department of Pediatric Hematology\nand Oncology, University of Ghent) for cytospins and microscopic analysis.\nSupported by the Beckman Institute at Caltech (for the Caltech Flow\nCytometry/Cell Sorting Facility), the National Institutes of Health (R01 CA98925 and R01 CA90233 to E.V.R.; R01 AI064590 to M.A.Y.) and the action\n'Return Grants' of the Belgian Science Policy (T.T.).\n\nAuthor Contributions: T.T., M.A.Y. and E.V.R. designed the experiments, analyzed data and wrote the manuscript; T.T. and M.A.Y. did the research.\n\nAccepted Version - nihms305533.pdf
Supplemental Material - ni1486-S1.pdf
", "abstract": "GATA-3 is essential for T cell development from the earliest stages. However, abundant GATA-3 can drive T lineage precursors to a non\u2013T cell fate, depending on Notch signaling and developmental stage. Here, overexpression of GATA-3 blocked the survival of pro\u2013T cells when Notch-Delta signals were present but enhanced viability in their absence. In fetal thymocytes at the double-negative 1 (DN1) stage and DN2 stage but not those at the DN3 stage, overexpression of GATA-3 rapidly induced respecification to the mast cell lineage with high frequency by direct transcriptional 'reprogramming'. Normal DN2 thymocytes also showed mast cell potential when interleukin 3 and stem cell factor were added in the absence of Notch signaling. Our results suggest a close relationship between the pro\u2013T cell and mast cell programs and a previously unknown function for Notch in T lineage fidelity.", "date": "2007-08", "date_type": "published", "publication": "Nature Immunology", "volume": "8", "number": "8", "publisher": "Nature Publishing Group", "pagerange": "845-855", "id_number": "CaltechAUTHORS:20150317-124107825", "issn": "1529-2908", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20150317-124107825", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Caltech Beckman Institute" }, { "agency": "NIH", "grant_number": "R01 CA98925" }, { "agency": "NIH", "grant_number": "R01 CA90233" }, { "agency": "NIH", "grant_number": "R01 AI064590" }, { "agency": "Belgian Science Policy" } ] }, "doi": "10.1038/ni1486", "pmcid": "PMC3140173", "primary_object": { "basename": "ni1486-S1.pdf", "url": "https://authors.library.caltech.edu/records/40nhk-d5430/files/ni1486-S1.pdf" }, "related_objects": [ { "basename": "nihms305533.pdf", "url": "https://authors.library.caltech.edu/records/40nhk-d5430/files/nihms305533.pdf" } ], "resource_type": "article", "pub_year": "2007", "author_list": "Taghon, Tom; Yui, Mary A.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/jj2dr-9fe51", "eprint_id": 9903, "eprint_status": "archive", "datestamp": "2023-08-22 06:18:05", "lastmod": "2023-10-23 17:18:46", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Franco-Christopher-B", "name": { "family": "Franco", "given": "Christopher B." } }, { "id": "Scripture-Adams-Dierdre-D", "name": { "family": "Scripture-Adams", "given": "Dierdre D." } }, { "id": "Proekt-Irina", "name": { "family": "Proekt", "given": "Irina" } }, { "id": "Taghon-Tom-N", "name": { "family": "Taghon", "given": "Tom" } }, { "id": "Weiss-Angela-H", "name": { "family": "Weiss", "given": "Angela H." } }, { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary A." }, "orcid": "0000-0002-3136-2181" }, { "id": "Adams-Stephanie-L", "name": { "family": "Adams", "given": "Stephanie L." } }, { "id": "Diamond-R-A", "name": { "family": "Diamond", "given": "Rochelle A." } }, { "id": "Rothenberg-E-V", "name": { "family": "Rothenberg", "given": "Ellen V." }, "orcid": "0000-0002-3901-347X" } ] }, "title": "Notch/Delta signaling constrains reengineering of pro-T cells by PU.1", "ispublished": "pub", "full_text_status": "public", "keywords": "gene regulation; hematopoiesis; lineage commitment; T cell development; transcription factors", "note": "\u00a9 2006 The National Academy of Sciences of the USA. \n\nEdited by Max D. Cooper, University of Alabama, Birmingham, AL, and approved June 19, 2006 (received for review February 11, 2006). Published online on July 31, 2006, 10.1073/pnas.0601188103. \n\nWe thank Thomas Graf for discussion of unpublished results; J.-C. Z\u00fa\u00f1iga-Pfl\u00fccker (University of Toronto, Toronto, Canada) for OP9 cell lines; Eric Davidson for insightful criticism of the manuscript and kind permission to use the ABI7900HT sequence detector; E.-S. David and C. C. Tydell (both at the California Institute of Technology) for PCR primers and help with quantitative PCR; Robert Butler for fine technical support; and Robin Condie, Ruben Bayon, Lorena Del Carmen Sandoval, Natasha Bouey, and Sherwin Chen for excellent care of mice. This work was supported by U.S. Public Health Service Grants R01 CA90233 and R01 CA98925 and by the DNA Sequencer Royalty Fund at California Institute of Technology. \n\nC.B.F. and D.D.S.-A. contributed equally to this work. \n\nAuthor contributions: D.D.S.-A., T.T., M.A.Y., and E.V.R. designed research; C.B.F., D.D.S.-A., I.P., T.T., A.H.W., M.A.Y., and S.L.A. performed research; C.B.F., D.D.S.-A., I.P., T.T., S.L.A., R.A.D., and E.V.R. analyzed data; E.V.R. wrote the paper; and A.H.W. provided crucial background studies. \n\nConflict of interest statement: No conflicts declared. \n\nThis paper was submitted directly (Track II) to the PNAS office. \n\nCorrection. PNAS, September 19, 2006, 103(38):14255.\n\nCorrection for Franco et al., Notch/Delta signaling constrains reengineering of pro-T cells by PU.1\nProceedings of the National Academy of Sciences Sep 2006, 103 (38) 14255; DOI: 10.1073/pnas.0607045103\n\nPublished - FRApnas06.pdf
Supplemental Material - FRApnas06fig10.pdf
Supplemental Material - FRApnas06fig11.pdf
Supplemental Material - FRApnas06fig5.pdf
Supplemental Material - FRApnas06fig6.pdf
Supplemental Material - FRApnas06fig7.pdf
Supplemental Material - FRApnas06fig8.pdf
Supplemental Material - FRApnas06fig9.pdf
Supplemental Material - FRApnas06methods.pdf
Supplemental Material - FRApnas06table.pdf
Erratum - FRApnas06corr.pdf
", "abstract": "PU.1 is essential for early stages of mouse T cell development but antagonizes it if expressed constitutively. Two separable mechanisms are involved: attenuation and diversion. Dysregulated PU.1 expression inhibits pro-T cell survival, proliferation, and passage through \u03b2-selection by blocking essential T cell transcription factors, signaling molecules, and Rag gene expression, which expression of a rearranged T cell antigen receptor transgene cannot rescue. However, Bcl2 transgenic cells are protected from this attenuation and may even undergo \u03b2-selection, as shown by PU.1 transduction of defined subsets of Bcl2 transgenic fetal thymocytes with differentiation in OP9-DL1 and OP9 control cultures. The outcome of PU.1 expression in these cells depends on Notch/Delta signaling. PU.1 can efficiently divert thymocytes toward a myeloid-like state with multigene regulatory changes, but Notch/Delta signaling vetoes diversion. Gene expression analysis distinguishes sets of critical T lineage regulatory genes with different combinatorial responses to PU.1 and Notch/Delta signals, suggesting particular importance for inhibition of E proteins, Myb, and/or Gfi1 (growth factor independence 1) in diversion. However, Notch signaling only protects against diversion of cells that have undergone T lineage specification after Thy-1 and CD25 up-regulation. The results imply that in T cell precursors, Notch/Delta signaling normally acts to modulate and channel PU.1 transcriptional activities during the stages from T lineage specification until commitment.", "date": "2006-08-08", "date_type": "published", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "volume": "103", "number": "32", "publisher": "National Academy of Sciences", "pagerange": "11993-11998", "id_number": "CaltechAUTHORS:FRApnas06", "issn": "0027-8424", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:FRApnas06", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R01 CA90233" }, { "agency": "NIH", "grant_number": "R01 CA98925" }, { "agency": "DNA Sequencer Royalty Fund, Caltech" } ] }, "doi": "10.1073/pnas.0601188103", "pmcid": "PMC1567686", "primary_object": { "basename": "FRApnas06table.pdf", "url": "https://authors.library.caltech.edu/records/jj2dr-9fe51/files/FRApnas06table.pdf" }, "related_objects": [ { "basename": "FRApnas06corr.pdf", "url": "https://authors.library.caltech.edu/records/jj2dr-9fe51/files/FRApnas06corr.pdf" }, { "basename": "FRApnas06fig5.pdf", "url": "https://authors.library.caltech.edu/records/jj2dr-9fe51/files/FRApnas06fig5.pdf" }, { "basename": "FRApnas06fig8.pdf", "url": "https://authors.library.caltech.edu/records/jj2dr-9fe51/files/FRApnas06fig8.pdf" }, { "basename": "FRApnas06fig9.pdf", "url": "https://authors.library.caltech.edu/records/jj2dr-9fe51/files/FRApnas06fig9.pdf" }, { "basename": "FRApnas06fig7.pdf", "url": "https://authors.library.caltech.edu/records/jj2dr-9fe51/files/FRApnas06fig7.pdf" }, { "basename": "FRApnas06methods.pdf", "url": "https://authors.library.caltech.edu/records/jj2dr-9fe51/files/FRApnas06methods.pdf" }, { "basename": "FRApnas06.pdf", "url": "https://authors.library.caltech.edu/records/jj2dr-9fe51/files/FRApnas06.pdf" }, { "basename": "FRApnas06fig10.pdf", "url": "https://authors.library.caltech.edu/records/jj2dr-9fe51/files/FRApnas06fig10.pdf" }, { "basename": "FRApnas06fig11.pdf", "url": "https://authors.library.caltech.edu/records/jj2dr-9fe51/files/FRApnas06fig11.pdf" }, { "basename": "FRApnas06fig6.pdf", "url": "https://authors.library.caltech.edu/records/jj2dr-9fe51/files/FRApnas06fig6.pdf" } ], "resource_type": "article", "pub_year": "2006", "author_list": "Franco, Christopher B.; Scripture-Adams, Dierdre D.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/cb76v-zsp02", "eprint_id": 74127, "eprint_status": "archive", "datestamp": "2023-08-19 17:17:48", "lastmod": "2023-10-24 22:07:36", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "David-Fung-E-S", "name": { "family": "David-Fung", "given": "Elizabeth-Sharon" } }, { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary A." }, "orcid": "0000-0002-3136-2181" }, { "id": "Morales-M", "name": { "family": "Morales", "given": "Marissa" } }, { "id": "Wang-Hua", "name": { "family": "Wang", "given": "Hua" } }, { "id": "Taghon-T", "name": { "family": "Taghon", "given": "Tom" } }, { "id": "Diamond-R-A", "name": { "family": "Diamond", "given": "Rochelle A." } }, { "id": "Rothenberg-E-V", "name": { "family": "Rothenberg", "given": "Ellen V." }, "orcid": "0000-0002-3901-347X" } ] }, "title": "Progression of regulatory gene expression states in fetal and adult pro-T-cell development", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2006 The Authors. Journal compilation \u00a9 2006 Blackwell Munksgaard. \n\nIssue online: 31 January 2006; Version of record online: 31 January 2006. \n\nThe authors wish to thank Michele Anderson, Christopher Franco, and Rashmi Pant for valuable contributions to the foundations of this review when they were in the Rothenberg Laboratory, Satoko Adachi for genomic DNA-specific primers and advice, Stephanie Adams for outstanding multiparameter fluorescence-activated cell sorting, and Ruben Bayon and the staff of the Office for Laboratory Animal Research for expert care of numerous mutant mouse strains used in the research. We also thank Lee Rowen (Institute for Systems Biology, Seattle) for sequencing multiple pro-T cell cDNA clones. M. M. gratefully acknowledges funding from the Minority Under-graduate Research Fellowships Program at the California Institute of Technology. The work discussed in this review was supported by grants from the USPHS, CA90233 and CA98925, by NASA grant NAG2-1588, by the Stowers Institute for Medical Research, and by the DNA Sequencer Royalty Fund at Caltech.\n\nAccepted Version - nihms605465.pdf
", "abstract": "Precursors entering the T-cell developmental pathway traverse a progression of states characterized by distinctive patterns of gene expression. Of particular interest are regulatory genes, which ultimately control the dwell time of cells in each state and establish the mechanisms that propel them forward to subsequent states. Under particular genetic and developmental circumstances, the transitions between these states occur with different timing, and environmental feedbacks may shift the steady-state accumulations of cells in each state. The fetal transit through pro-T-cell stages is faster than in the adult and subject to somewhat different genetic requirements. To explore causes of such variation, this review presents previously unpublished data on differentiation gene activation in pro-T cells of pre-T-cell receptor-deficient mutant mice and a quantitative comparison of the profiles of transcription factor gene expression in pro-T-cell subsets of fetal and adult wildtype mice. Against a background of consistent gene expression, several regulatory genes show marked differences between fetal and adult expression profiles, including those encoding two basic helix-loop-helix antagonist Id factors, the Ets family factor SpiB and the Notch target gene Deltex1. The results also reveal global differences in regulatory alterations triggered by the first T-cell receptor-dependent selection events in fetal and adult thymopoiesis.", "date": "2006-02", "date_type": "published", "publication": "Immunological Reviews", "volume": "209", "number": "1", "publisher": "Wiley", "pagerange": "212-236", "id_number": "CaltechAUTHORS:20170207-082859641", "issn": "0105-2896", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170207-082859641", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Caltech" }, { "agency": "NIH", "grant_number": "CA90233" }, { "agency": "NIH", "grant_number": "CA98925" }, { "agency": "NASA", "grant_number": "NAG2-1588" }, { "agency": "Stowers Institute for Medical Research" }, { "agency": "DNA Sequencer Royalty Fund, Caltech" } ] }, "doi": "10.1111/j.0105-2896.2006.00355.x", "pmcid": "PMC4157939", "primary_object": { "basename": "nihms605465.pdf", "url": "https://authors.library.caltech.edu/records/cb76v-zsp02/files/nihms605465.pdf" }, "resource_type": "article", "pub_year": "2006", "author_list": "David-Fung, Elizabeth-Sharon; Yui, Mary A.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/1qj4y-hdz71", "eprint_id": 74126, "eprint_status": "archive", "datestamp": "2023-08-19 17:10:18", "lastmod": "2023-10-24 22:07:28", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Taghon-T", "name": { "family": "Taghon", "given": "Tom" } }, { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary A." }, "orcid": "0000-0002-3136-2181" }, { "id": "Pant-R", "name": { "family": "Pant", "given": "Rashmi" } }, { "id": "Diamond-R-A", "name": { "family": "Diamond", "given": "Rochelle A." } }, { "id": "Rothenberg-E-V", "name": { "family": "Rothenberg", "given": "Ellen V." }, "orcid": "0000-0002-3901-347X" } ] }, "title": "Developmental and Molecular Characterization of Emerging \u03b2- and \u03b3\u03b4-Selected Pre-T Cells in the Adult Mouse Thymus", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2006 Elsevier Inc. \n\nReceived 4 August 2005, Revised 6 November 2005, Accepted 30 November 2005, Available online 17 January 2006. Published: January 17, 2006. \n\nWe thank Michele K. Anderson and Elizabeth-Sharon David for primers; Ruben Bayon for animal care; and Stephanie Adams and Pat Koen of the Caltech Flow Cytometry/Cell Sorting Facility. We apologize to colleagues whose work we could not cite. This work was supported by grants from the NIH (R01 CA98925 and R01 CA90233).\n\nSupplemental Material - mmc1.pdf
", "abstract": "The first checkpoint in T cell development, \u03b2 selection, has remained incompletely characterized for lack of specific surface markers. We show that CD27 is upregulated in DN3 thymocytes initiating \u03b2 selection, concomitant with intracellular TCR-\u03b2 expression. Clonal analysis determined that CD27^(high) DN3 cells generate CD4^+CD8^+ progeny with more than 90% efficiency, faster and more efficiently than the CD27^(low) majority. CD27 upregulation also occurs in \u03b3\u03b4-selected DN3 thymocytes in TCR-\u03b2\u2212/\u2212 mice and in IL2-GFP transgenic reporter mice where GFP marks the earliest emerging TCR-\u03b3\u03b4 cells from DN3 thymocytes. With CD27 to distinguish pre- and postselection DN3 cells, a detailed gene expression analysis defined regulatory changes associated with checkpoint arrest, with \u03b2 selection, and with \u03b3\u03b4 selection. \u03b3\u03b4 selection induces higher CD5, Egr, and Runx3 expression as compared to \u03b2 selection, but it triggers less proliferation. Our results also reveal differences in Notch/Delta dependence at the earliest stages of divergence between developing \u03b1\u03b2 and \u03b3\u03b4 T-lineage cells.", "date": "2006-01", "date_type": "published", "publication": "Immunity", "volume": "24", "number": "1", "publisher": "Elsevier", "pagerange": "53-64", "id_number": "CaltechAUTHORS:20170207-080106709", "issn": "1074-7613", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170207-080106709", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R01 CA98925" }, { "agency": "NIH", "grant_number": "R01 CA90233" } ] }, "doi": "10.1016/j.immuni.2005.11.012", "primary_object": { "basename": "mmc1.pdf", "url": "https://authors.library.caltech.edu/records/1qj4y-hdz71/files/mmc1.pdf" }, "resource_type": "article", "pub_year": "2006", "author_list": "Taghon, Tom; Yui, Mary A.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/6e6h3-6em15", "eprint_id": 74313, "eprint_status": "archive", "datestamp": "2023-08-19 14:39:18", "lastmod": "2023-10-24 22:28:27", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary A." }, "orcid": "0000-0002-3136-2181" }, { "id": "Rothenberg-E-V", "name": { "family": "Rothenberg", "given": "Ellen V." }, "orcid": "0000-0002-3901-347X" } ] }, "title": "Deranged Early T Cell Development in Immunodeficient Strains of Nonobese Diabetic Mice", "ispublished": "pub", "full_text_status": "restricted", "note": "\u00a9 2004 The American Association of Immunologists, Inc. \n\nReceived for publication May 27, 2004. Accepted for publication August 12, 2004. \n\nWe thank R. Bayon for excellent mouse care, R. Diamond and P. Koen (Caltech Flow Cytometry Facility) for advice and cell sorting, Dr. M. K. Anderson (University of Toronto) for Heb-alt primers, and Dr. E. Robey (University of California-Berkeley) for providing B6-Mhc^(null) mice. \n\nThis work was supported by National Institutes of Health Grants AG13108 and CA90233 (to E.V.R.).", "abstract": "NOD mice exhibit defects in T cell functions that have been postulated to contribute to diabetes susceptibility in this strain. However, early T cell development in NOD mice has been largely unexplored. NOD mice with the scid mutation and Rag1 deficiency were analyzed for pre-T cell development in the NOD genetic background. These strains reveal an age-dependent, programmed breakdown in \u03b2 selection checkpoint enforcement. At 5\u20138 wk of age, even in the absence of TCR\u03b2 expression, CD4^+ and CD4^+CD8^+ blasts appear spontaneously. However, these breakthrough cells fail to restore normal thymic cellularity. The breakthrough phenotype is recessive in hybrid (NOD\u00d7B6)F_1-scid and -Rag1^(null) mice. The breakthrough cells show a mosaic phenotype with respect to components of the \u03b2 selection program. They mimic normal \u03b2 selection by up-regulating germline TCR-C\u03b1 transcripts, CD2, and Bcl-x_L and down-regulating Bcl-2. However, they fail to down-regulate transcription factors HEB-alt and Hes1 and initially express aberrantly high levels of Spi-B, c-kit (CD117), and IL-7R\u03b1. Other genes examined distinguish this form of breakthrough from previously reported models. Some of the abnormalities appear first in a cohort of postnatal thymocytes as early as the double-negative 2/double-negative 3 transitional stage. Thus, our results reveal an NOD genetic defect in T cell developmental programming and checkpoint control that permits a subset of the normal outcomes of pre-TCR signaling to proceed even in the absence of TCR\u03b2 rearrangement. Furthermore, this breakthrough may initiate thymic lymphomagenesis that occurs with high frequency in both NOD-scid and -Rag1^(null) mice.", "date": "2004-11-01", "date_type": "published", "publication": "Journal of Immunology", "volume": "173", "number": "9", "publisher": "American Association of Immunologists", "pagerange": "5381-5391", "id_number": "CaltechAUTHORS:20170215-075718505", "issn": "0022-1767", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170215-075718505", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "AG13108" }, { "agency": "NIH", "grant_number": "CA90233" } ] }, "doi": "10.4049/jimmunol.173.9.5381", "resource_type": "article", "pub_year": "2004", "author_list": "Yui, Mary A. and Rothenberg, Ellen V." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/kfycc-s6w89", "eprint_id": 74314, "eprint_status": "archive", "datestamp": "2023-08-19 13:28:10", "lastmod": "2023-10-24 22:28:30", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary A." }, "orcid": "0000-0002-3136-2181" }, { "id": "Sharp-L-L", "name": { "family": "Sharp", "given": "Leslie L." } }, { "id": "Havran-W-L", "name": { "family": "Havran", "given": "Wendy L." } }, { "id": "Rothenberg-E-V", "name": { "family": "Rothenberg", "given": "Ellen V." }, "orcid": "0000-0002-3901-347X" } ] }, "title": "Preferential Activation of an IL-2 Regulatory Sequence Transgene in TCR\u03b3\u03b4 and NKT Cells: Subset-Specific Differences in IL-2 Regulation", "ispublished": "pub", "full_text_status": "restricted", "note": "\u00a9 2004 The American Association of Immunologists, Inc. \n\nReceived July 23, 2003. Accepted January 29, 2004. \n\nWe thank Dr. Hua Gu for generously providing us with the IL-2-GFP^(ki)-Rag2^(\u2212/\u2212) animals. Also, we thank Shelley Diamond and Patrick Koen of the Caltech Flow Cytometry and Sorting Facility for cell sorting expertise and Bruce Kennedy and other members of the Caltech Transgenic Animal Facility for maintenance of the animals used in this study. \n\nThis work was supported by National Institutes of Health Grants AG13108 (to E.V.R.) and AI036964 (to W.L.H.).", "abstract": "A transgene with 8.4-kb of regulatory sequence from the murine IL-2 gene drives consistent expression of a green fluorescent protein (GFP) reporter gene in all cell types that normally express IL-2. However, quantitative analysis of this expression shows that different T cell subsets within the same mouse show divergent abilities to express the transgene as compared with endogenous IL-2 genes. TCR\u03b3\u03b4 cells, as well as \u03b1\u03b2TCR-NKT cells, exhibit higher in vivo transgene expression levels than TCR\u03b1\u03b2 cells. This deviates from patterns of normal IL-2 expression and from expression of an IL-2-GFP knock-in. Peripheral TCR\u03b3\u03b4 cells accumulate GFP RNA faster than endogenous IL-2 RNA upon stimulation, whereas TCR\u03b1\u03b2 cells express more IL-2 than GFP RNA. In TCR\u03b3\u03b4 cells, IL-2-producing cells are a subset of the GFP-expressing cells, whereas in TCR\u03b1\u03b2 cells, endogenous IL-2 is more likely to be expressed without GFP. These results are seen in multiple independent transgenic lines and thus reflect functional properties of the transgene sequences, rather than copy number or integration site effects. The high ratio of GFP: endogenous IL-2 gene expression in transgenic TCR\u03b3\u03b4 cells may be explained by subset-specific IL-2 gene regulatory elements mapping outside of the 8.4-kb transgene regulatory sequence, as well as accelerated kinetics of endogenous IL-2 RNA degradation in TCR\u03b3\u03b4 cells. The high levels and percentages of transgene expression in thymic and splenic TCR\u03b3\u03b4 and NKT cells, as well as skin TCR\u03b3\u03b4-dendritic epidermal T cells, indicate that the IL-2-GFP-transgenic mice may provide valuable tracers for detecting developmental and activation events in these lineages.", "date": "2004-04-15", "date_type": "published", "publication": "Journal of Immunology", "volume": "172", "number": "8", "publisher": "American Association of Immunologists", "pagerange": "4691-4699", "id_number": "CaltechAUTHORS:20170215-085418955", "issn": "0022-1767", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170215-085418955", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "AG13108" }, { "agency": "NIH", "grant_number": "AI036964" } ] }, "doi": "10.4049/jimmunol.172.8.4691", "resource_type": "article", "pub_year": "2004", "author_list": "Yui, Mary A.; Sharp, Leslie L.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/5bzfe-7h572", "eprint_id": 74701, "eprint_status": "archive", "datestamp": "2023-08-19 10:37:51", "lastmod": "2023-10-24 22:52:02", "type": "book_section", "metadata_visibility": "show", "creators": { "items": [ { "id": "Rothenberg-E-V", "name": { "family": "Rothenberg", "given": "Ellen V." }, "orcid": "0000-0002-3901-347X" }, { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary A." }, "orcid": "0000-0002-3136-2181" }, { "id": "Telfer-J-C", "name": { "family": "Telfer", "given": "Janice C." } } ] }, "title": "T-Cell Developmental Biology", "ispublished": "unpub", "full_text_status": "public", "abstract": "[no abstract]", "date": "2003", "date_type": "published", "publisher": "Lippincott Williams & Wilkins", "place_of_pub": "Philadelphia, PA", "pagerange": "259-301", "id_number": "CaltechAUTHORS:20170303-122145058", "isbn": "9780781735148", "book_title": "Fundamental Immunology, Fifth Edition", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170303-122145058", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "contributors": { "items": [ { "id": "Paul-W-E", "name": { "family": "Paul", "given": "William E." } } ] }, "resource_type": "book_section", "pub_year": "2003", "author_list": "Rothenberg, Ellen V.; Yui, Mary A.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/m5bx6-nnk88", "eprint_id": 74223, "eprint_status": "archive", "datestamp": "2023-08-19 07:17:43", "lastmod": "2023-10-24 22:13:51", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary A." }, "orcid": "0000-0002-3136-2181" }, { "id": "Hern\u00e1ndez-Hoyos-G", "name": { "family": "Hern\u00e1ndez-Hoyos", "given": "Gabriela" } }, { "id": "Rothenberg-E-V", "name": { "family": "Rothenberg", "given": "Ellen V." }, "orcid": "0000-0002-3901-347X" } ] }, "title": "A New Regulatory Region of the IL-2 Locus That Confers Position-Independent Transgene Expression", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2001 American Association of Immunologists. \n\nWe thank Stephen Hedrick for kindly providing the plasmid containing the human \u03b2-globin 3\u2032 splicing and poly(A) addition sites and Michael Nishimura for the melanoma cell line MCA102. We gratefully acknowledge help from Robert Chen for screening the genomic library for the IL-2 promoter clone and to Xiao Sun for sequencing assistance. Shelley Diamond and Pat Koen of the Flow Cytometry Core Facility provided invaluable help with flow cytometry and cell sorting. We also thank Shirley Pease, Xin Yu, Bruce Kennedy, and Alba Granados of the Caltech Transgenic and Knockout Core Facility for the generation and maintenance of the transgenic mice. All primers were made at the Caltech Biopolymer Synthesis Facility, and sequencing was performed at the Caltech DNA Sequencing Core Facility. \n\nThis work was supported by National Institutes of Health Grant AG13108 and the Stowers Institute for Medical Research.", "abstract": "Although the promoter/enhancer of the IL-2 gene mediates inducible reporter gene expression in vitro, it cannot drive consistent expression in transgenic mice. The location and existence of any regulatory elements that could open the IL-2 locus in vivo have remained unknown, preventing analysis of IL-2 regulation in developmental contexts. In this study, we report the identification of such a regulatory region, marked by novel DNase-hypersensitive sites upstream of the murine IL-2 promoter in unstimulated and stimulated T cells. Inclusion of most of these sites in an 8.4-kb IL-2 promoter green fluorescent protein transgene gives locus control region-like activity. Expression is efficient, tissue specific, and position independent. This transgene is expressed not only in peripheral T cells, but also in immature thymocytes and thymocytes undergoing positive selection, in agreement with endogenous IL-2 expression. In contrast, a 2-kb promoter green fluorescent protein transgene, lacking the new hypersensitive sites, is expressed in only a few founder lines, and expression is dysregulated in CD8+ cells. Thus, the 6.4 kb of additional upstream IL-2 sequence contains regulatory elements that provide integration site independence and differential regulation of transgene expression in CD8 vs CD4 cells.", "date": "2001-02-01", "date_type": "published", "publication": "Journal of Immunology", "volume": "166", "number": "3", "publisher": "American Association of Immunologists", "pagerange": "1730-1739", "id_number": "CaltechAUTHORS:20170213-074814967", "issn": "0022-1767", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170213-074814967", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "AG13108" }, { "agency": "Stowers Institute for Medical Research" } ] }, "doi": "10.4049/jimmunol.166.3.1730", "resource_type": "article", "pub_year": "2001", "author_list": "Yui, Mary A.; Hern\u00e1ndez-Hoyos, Gabriela; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/m89za-wdh84", "eprint_id": 74704, "eprint_status": "archive", "datestamp": "2023-08-19 03:22:34", "lastmod": "2023-10-24 22:52:11", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Morel-L", "name": { "family": "Morel", "given": "L." } }, { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "M. A." }, "orcid": "0000-0002-3136-2181" }, { "id": "Wakeland-E-K", "name": { "family": "Wakeland", "given": "E. K." } } ] }, "title": "La contribution des mod\u00e8les murins \u00e0 la compr\u00e9hension des maladies immunitaires", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 1998 Published by Elsevier Masson SAS.", "abstract": "La pr\u00e9disposition aux maladies auto-immunes est influenc\u00e9e par de nombreux g\u00e8nes ainsi que par des facteurs d'environnement. \u00c0 cause de la tr\u00e8s grande complexit\u00e9 de ces syst\u00e8mes, il est devenu \u00e9vident que les mod\u00e8les animaux qui \u00e9taient couramment utilis\u00e9s dans les travaux d'immunopathologie pouvaient constituer des outils remarquables pour l'analyse g\u00e9n\u00e9tique de la pr\u00e9disposition \u00e0 l'auto-immunit\u00e9.", "date": "1998-10", "date_type": "published", "publication": "Annales de l'Institut Pasteur / Actualit\u00e9s", "volume": "9", "number": "4", "publisher": "Elsevier Masson SAS", "pagerange": "351-359", "id_number": "CaltechAUTHORS:20170303-130917732", "issn": "0924-4204", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170303-130917732", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1016/S0924-4204(99)80014-6", "resource_type": "article", "pub_year": "1998", "author_list": "Morel, L.; Yui, M. A.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/b2e9h-6xv79", "eprint_id": 74712, "eprint_status": "archive", "datestamp": "2023-08-19 01:53:05", "lastmod": "2023-10-24 22:52:34", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Wakeland-E-K", "name": { "family": "Wakeland", "given": "Edward" } }, { "id": "Morel-L", "name": { "family": "Morel", "given": "Laurence" } }, { "id": "Achey-K", "name": { "family": "Achey", "given": "Karen" } }, { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary" }, "orcid": "0000-0002-3136-2181" }, { "id": "Longmate-J-A", "name": { "family": "Longmate", "given": "Jeff" } } ] }, "title": "Speed congenics: a classic technique in the fast lane (relatively speaking)", "ispublished": "pub", "full_text_status": "restricted", "note": "\u00a9 1997 Elsevier Ltd.", "abstract": "Marker-assisted selection protocol (MASP)-based strategies produce congenic strains with the target gene contained on clearly defined donor-derived genomic intervals in less than half the number of generations required by the classic protocol, Thus, the quality and speed of congenic strain construction are enhanced by this methodology. Here, Edward Wakeland and colleagues compare various MASP-based strategies and discuss their advantages with reference to immunological traits.", "date": "1997-10", "date_type": "published", "publication": "Immunology Today", "volume": "18", "number": "10", "publisher": "Elsevier", "pagerange": "472-477", "id_number": "CaltechAUTHORS:20170303-140538819", "issn": "0167-5699", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170303-140538819", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1016/S0167-5699(97)01126-2", "resource_type": "article", "pub_year": "1997", "author_list": "Wakeland, Edward; Morel, Laurence; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/bwf8h-bjj33", "eprint_id": 74713, "eprint_status": "archive", "datestamp": "2023-08-22 11:47:59", "lastmod": "2023-10-24 22:52:40", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Wakeland-E-K", "name": { "family": "Wakeland", "given": "Edward K." } }, { "id": "Morel-L", "name": { "family": "Morel", "given": "Laurence" } }, { "id": "Mohan-C", "name": { "family": "Mohan", "given": "Chandra" } }, { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary" }, "orcid": "0000-0002-3136-2181" } ] }, "title": "Genetic dissection of lupus nephritis in murine models of SLE", "ispublished": "pub", "full_text_status": "restricted", "keywords": "Lupus nephritis; systemic lupus erythematosus; murine models; genetics", "note": "\u00a9 1997 Plenum Publishing Corporation. \n\nAccepted: April 16, 1997.", "abstract": "Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with extremely heterogeneous clinical features, varying in pathogenicity from mild forms of the disease to those that advance relentlessly leading to progressive end organ damage. The underlying autoimmune disorder can express as a variety of immunologic abnormalities but generally results in the production of autoantibodies primarily directed against a spectrum of nuclear antigens. Much of the pathogenicity of SLE results from inflammatory processes initiated as a consequence of either the deposition of immune complexes or the targeting of autoantibodies to various anatomic sites. The most serious clinical consequences of SLE result from immune complex deposition in the kidney, resulting in lupus nephritis and culminating in kidney failure.", "date": "1997-07", "date_type": "published", "publication": "Journal of Clinical Immunology", "volume": "17", "number": "4", "publisher": "Springer Verlag", "pagerange": "272-281", "id_number": "CaltechAUTHORS:20170303-140645475", "issn": "0271-9142", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170303-140645475", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1023/A:1027370514198", "resource_type": "article", "pub_year": "1997", "author_list": "Wakeland, Edward K.; Morel, Laurence; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/yywab-sgc62", "eprint_id": 74715, "eprint_status": "archive", "datestamp": "2023-08-19 00:53:21", "lastmod": "2023-10-24 22:52:45", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary A." }, "orcid": "0000-0002-3136-2181" }, { "id": "Wakeland-E-K", "name": { "family": "Wakeland", "given": "Edward K." } } ] }, "title": "Mouse chromosome 3", "ispublished": "pub", "full_text_status": "restricted", "note": "\u00a9 Springer-Verlag New York Inc 1997. \n\nReceived: 2 October 1996.", "abstract": "During the past year, more than 300 new loci have been assigned to Chromosome (Chr) 3, including 25 new genes. The remainder are simple sequence length polymorphisms (SSLP), anonymous marker loci, or cytogenetic markers. The Chr 3 map now includes over 700 markers. As in previous reports, new loci have been integrated into the previous map with the primary objective of maintaining an accurate order. Distances were adjusted to assume a length of 95 centiMorgans (cM) for the chromosome.", "date": "1997-01", "date_type": "published", "publication": "Mammalian Genome", "volume": "7", "number": "S1", "publisher": "Springer", "pagerange": "S45-S59", "id_number": "CaltechAUTHORS:20170303-142449318", "issn": "0938-8990", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170303-142449318", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1007/s003359900315", "resource_type": "article", "pub_year": "1997", "author_list": "Yui, Mary A. and Wakeland, Edward K." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/djce2-qj397", "eprint_id": 74717, "eprint_status": "archive", "datestamp": "2023-08-20 07:33:12", "lastmod": "2023-10-24 22:52:49", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "M. A." }, "orcid": "0000-0002-3136-2181" }, { "id": "Muralidharan-K", "name": { "family": "Muralidharan", "given": "K." } }, { "id": "Moreno-Altamirano-B", "name": { "family": "Moreno-Altamirano", "given": "B." } }, { "id": "Perrin-G", "name": { "family": "Perrin", "given": "G." } }, { "id": "Chestnut-K", "name": { "family": "Chestnut", "given": "K." } }, { "id": "Wakeland-E-K", "name": { "family": "Wakeland", "given": "E. K." } } ] }, "title": "Production of congenic mouse strains carrying NOD-derived diabetogenic genetic intervals: An approach for the genetic dissection of complex traits", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 Springer-Verlag 1996. \n\nReceived: 01 September 1995. Accepted: 20 December 1995.", "abstract": "Insulin-dependent (Type 1) diabetes (IDD) in the NOD mouse is inherited as a complex polygenic trait making the identification of susceptibility genes difficult. Currently none of the non-MHC IDD susceptibility genes in NOD have been identified. In this paper we describe the congenic mouse approach that we are using for the dissection of complex traits, such as IDD. We produced a series of six congenic strains carrying NOD-derived diabetogenic genomic intervals, which were previously identified by linkage analysis, on a resistant background. These congenic strains were produced for the purpose of characterizing the function of each of these genes, alone and in combinations, in IDD pathogenesis and to allow fine mapping of the NOD IDD susceptibility genes. Histological examination of pancreata from 6 to 8-month-old congenic mice reveals that intervals on Chromosomes (Chrs) 1 and 17, but not 3, 6, and 11, contain NOD-derived genes that can increase the trafficking of mononuclear cells into the pancreas. Insulitis was observed only very rarely, even in older congenic mice, indicating that multiple genes are required for this phenotype. These results demonstrate the utility of this congenic approach for the study of complex genetic traits.", "date": "1996-05", "date_type": "published", "publication": "Mammalian Genome", "volume": "7", "number": "5", "publisher": "Springer", "pagerange": "331-334", "id_number": "CaltechAUTHORS:20170303-142730717", "issn": "0938-8990", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170303-142730717", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1007/s003359900097", "resource_type": "article", "pub_year": "1996", "author_list": "Yui, M. A.; Muralidharan, K.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/dw8cr-ata72", "eprint_id": 74726, "eprint_status": "archive", "datestamp": "2023-08-20 00:18:47", "lastmod": "2023-10-24 22:53:13", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary A." }, "orcid": "0000-0002-3136-2181" }, { "id": "Brissette-W-H", "name": { "family": "Brissette", "given": "William H." } }, { "id": "Brennan-D-C", "name": { "family": "Brennan", "given": "Daniel C." } }, { "id": "Wuthrich-R-P", "name": { "family": "Wuthrich", "given": "Rudolf P." } }, { "id": "Rubin-Kelley-V-E", "name": { "family": "Rubin-Kelley", "given": "Vicki E." } } ] }, "title": "Increased macrophage colony-stimulating factor in neonatal and adult autoimmune MRL-lpr mice", "ispublished": "pub", "full_text_status": "restricted", "note": "\u00a9 American Association of Pathologists. \n\nAccepted for publication March 12, 1991. \n\nThe authors thank Drs. C. B. Carpenter and David L. Perkins for carefully reviewing this manuscript. \n\nSupported by NIH grants DK-36149, DK-40839, and CA-48626 (to Vicki Rubin-Kelley), Al-07918 (to Daniel Brennan), and a grant from the Jules and Gwen Knapp Chartable Foundation. Rudolph Wuthrich is a recipient of a grant from the Swiss National Science Foundation.", "abstract": "Abnormal macrophages in MRL-lpr mice are implicated in the pathogenesis of autoimmune disease. These mice die of lupus nephritis by 5 to 6 months of age. This study reports that MRL-lpr mice have an increased level of circulating macrophage colony-stimulating factor (M-CSF) detectable as early as 1 week of age. Macrophage colony-stimulating factor decreased between 2 and 4 months and then steadily increased beginning at 4 months of age. In contrast, M-CSF was not detected in sera from congenic MRL-++ mice, normal C3H/FeJ mice, two other mouse strains with the lpr gene (B6-lpr and C3H-lpr), or another lupus model, the NZB/W mouse. These observations indicate that the lpr gene alone is not responsible for inducing this growth factor, and elevated M-CSF is not required for all forms of murine lupus. The entire source of serum M-CSF is not clear. The unique T cells regulated by the lpr gene are not responsible for the increased serum M-CSF levels, as no M-CSFs could be detected in supernatants from cultured lymph nodes from MRL-lpr mice, and the steady-state levels of M-CSF mRNA in lymph nodes and spleens in MRL-lpr, C3H-lpr mice and in their respective congenic strains were similar. The steady-state M-CSF mRNA transcripts in liver, lung, and bone marrow in MRL-lpr, MRL-++, and C3H/FeJ mice were also similar. Macrophage colony-stimulating factor transcripts were clearly elevated in the kidneys of MRL-lpr mice, suggesting a renal source of circulating M-CSF. The increase of M-CSF might be responsible for the increased numbers and enhanced functions of macrophages, which in turn cause tissue destruction in MRL-lpr mice.", "date": "1991-08", "date_type": "published", "publication": "American Journal of Pathology", "volume": "139", "number": "2", "publisher": "Elsevier", "pagerange": "255-261", "id_number": "CaltechAUTHORS:20170303-145305364", "issn": "0002-9440", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170303-145305364", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "DK-36149" }, { "agency": "NIH", "grant_number": "DK-40839" }, { "agency": "NIH", "grant_number": "CA-48626" }, { "agency": "NIH", "grant_number": "Al-07918" }, { "agency": "Jules and Gwen Knapp Chartable Foundation" }, { "agency": "Swiss National Science Foundation (SNSF)" } ] }, "pmcid": "PMC1886069", "resource_type": "article", "pub_year": "1991", "author_list": "Yui, Mary A.; Brissette, William H.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/0az9z-9sh98", "eprint_id": 74723, "eprint_status": "archive", "datestamp": "2023-08-19 22:38:07", "lastmod": "2023-10-24 22:53:06", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Pankewycz-O-G", "name": { "family": "Pankewycz", "given": "Oleh G." } }, { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary" }, "orcid": "0000-0002-3136-2181" }, { "id": "Kelley-V-E", "name": { "family": "Kelley", "given": "Vicki E." } }, { "id": "Strom-T-B", "name": { "family": "Strom", "given": "Terry B." } } ] }, "title": "The cascading, interrelated roles of interleukin-1, interleukin-2, and interleukin-6 in murine anti-CD3-driven T cell proliferation", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 1990 Elsevier Inc. \n\nReceived 8 May 1989, Accepted 7 November 1989. \n\nThis work was supported by NIH Grants AM 35149, DK 33929, and AI 122882.", "abstract": "T cell stimulation occurs following interaction of T cell receptor (TcR) with processed antigen presented by autologous accessory cells (AC). The effects of antigen stimulation on T cells are mimicked by monoclonal antibodies (Mabs) defining proteins of the TcR-CD3 complex. In this study, we examine the roles of T cell density, AC density, divalent and polyvalent forms of anti-CD3 Mab, and the cytokines interleukin (IL)-1, IL-2, and IL-6 in T cell activation and proliferation. Stringently AC-depleted T cells do not proliferate in response to con A or divalent anti-CD3; however, polyvalent anti-CD3 provides a powerful signal for isolated resting T cell proliferation. Recombinant (r)IL-2 strongly amplifies T cell proliferation in response to anti-CD3, whereas rIL-1 exerts no direct effects on anti-CD3-stimulated T cells. In the presence of AC, however, rIL-1 augments T cell proliferation to anti-CD3. Recombinant IL-6 promotes T cell proliferation among T cells stimulated with polyvalent but not divalent anti-CD3. As deduced by Northern blot analysis, rIL-1 increases cytoplasmic levels of IL-6 mRNA in AC. Recombinant IL-6, in turn, amplifies the accumulation of stable IL-2 transcripts in purified T cells stimulated with polyvalent anti-CD3. Hence, IL-1, IL-6, and IL-2 support T cell proliferation through cascading effects at the level of gene transcription. The cytokines evaluated in this study, however, do not fully reconstitute AC functions in promoting anti-CD3 Mab T cell proliferation.", "date": "1990-04", "date_type": "published", "publication": "Clinical Immunology and Immunopathology", "volume": "55", "number": "1", "publisher": "Elsevier", "pagerange": "67-85", "id_number": "CaltechAUTHORS:20170303-144045044", "issn": "0090-1229", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170303-144045044", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "AM 35149" }, { "agency": "NIH", "grant_number": "DK 33929" }, { "agency": "NIH", "grant_number": "AI 122882" } ] }, "doi": "10.1016/0090-1229(90)90069-3", "resource_type": "article", "pub_year": "1990", "author_list": "Pankewycz, Oleh G.; Yui, Mary; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/yrkg8-0wm05", "eprint_id": 74721, "eprint_status": "archive", "datestamp": "2023-08-19 22:27:54", "lastmod": "2023-10-24 22:53:01", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Wuthrich-R-P", "name": { "family": "Wuthrich", "given": "Rudolf P." } }, { "id": "Glimcher-L-H", "name": { "family": "Glimcher", "given": "Laurie H." } }, { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary A." }, "orcid": "0000-0002-3136-2181" }, { "id": "Jevnikar-A-M", "name": { "family": "Jevnikar", "given": "Anthony M." } }, { "id": "Dumas-S-E", "name": { "family": "Dumas", "given": "Stephanie E." } }, { "id": "Kelley-V-E", "name": { "family": "Kelley", "given": "Vicki E." } } ] }, "title": "MHC class II, antigen presentation and tumor necrosis factor in renal tubular epithelial cells", "ispublished": "pub", "full_text_status": "restricted", "note": "\u00a9 1990 International Society of Nephrology. \n\nAccepted: September 1, 1989. Received in revised form: August 25, 1989. Received: May 26, 1989. \n\nPart of this work was published in abstract form (Kidney Int 35:366, 1989, and FASEB J 3:A301, 1989). This work was supported by NIH grants DK-40839 (V.E.K. and L.H.G.) and DK-36149 (V.E.K.), and by the Jules and Gwen Knapp Charitable Foundation. R.P.W. is the recipient of a grant from the Swiss National Science Foundation. A.M.J. is the recipient of a fellowship from the Medical Research Council of Canada. We thank Drs. S. Gullans and R.C. Stanton for helpful suggestions, and Dr. C.B. Carpenter for reviewing the manuscript. We also thank Genentech (South San Francisco, California, USA) for kindly supplying us with recombinant IFN-\u03b3 and rTNF-\u03b1, and Hoffmann-La Roche (Nutley, New Jersey, USA) and Pfizer (Groton, Connecticut, USA) for rIL-1\u03b1.", "abstract": "MHC class II, antigen presentation and tumor necrosis factor in renal tubular epithelial cells. Proximal tubular (PT) epithelial cells express MHC class II (la) antigens in immunologically-mediated renal injury. To study the role of PT as accessory cells, we generated several murine PT-like epithelial cell lines by transformation with origin-defective SV40 DNA. These transformed cell lines display typical alkaline phosphatase and \u03b3glutamyl-transpeptidase enzyme activity, proliferation to epidermal growth factor (EGF) and sodium-dependent glucose uptake. Clonal lines of transformed tubular cells from both normal C3H/FeJ and autoimmune MRL-lpr mice do not constitutively express la antigens or mRNA for class II. However, stimulation with recombinant interferon-\u03b3 (rIFN-\u03b3) induces la mRNA and surface product in the cell lines. These la-positive cells can process and present hen egg-white lysozyme (HEL) to antigen-specific Iak-restricted T cell hybrids. Unstimulated tubular cells do not express detectable IL-1\u03b1, IL-1\u03b2, TNF-\u03b1, or IL-6 mRNA. However, stimulation with IL-1\u03b1 or LPS induces TNF-\u03b1 transcripts. We conclude that these cell lines have characteristics most consistent with a proximal tubular origin. They also bear characteristics of accessory cells such as processing and presentation of antigen and TNF-\u03b1 gene expression. We speculate that PT have the capacity to participate in the pathogenesis of immune renal injury.", "date": "1990-02", "date_type": "published", "publication": "Kidney International", "volume": "37", "number": "2", "publisher": "Elsevier", "pagerange": "783-792", "id_number": "CaltechAUTHORS:20170303-143537838", "issn": "0085-2538", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170303-143537838", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "DK-40839" }, { "agency": "NIH", "grant_number": "DK-36149" }, { "agency": "Jules and Gwen Knapp Charitable Foundation" }, { "agency": "Swiss National Science Foundation (SNSF)" }, { "agency": "Medical Research Council of Canada" } ] }, "doi": "10.1038/ki.1990.46", "resource_type": "article", "pub_year": "1990", "author_list": "Wuthrich, Rudolf P.; Glimcher, Laurie H.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/vx0gn-d3d23", "eprint_id": 74727, "eprint_status": "archive", "datestamp": "2023-08-19 22:04:50", "lastmod": "2023-10-24 22:53:17", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Brennan-D-C", "name": { "family": "Brennan", "given": "Daniel C." } }, { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary A." }, "orcid": "0000-0002-3136-2181" }, { "id": "Wuthrich-R-P", "name": { "family": "Wuthrich", "given": "Rudolf P." } }, { "id": "Rubin-Kelley-V-E", "name": { "family": "Kelley", "given": "Vicki E." } } ] }, "title": "Tumor necrosis factor and IL-1 in New Zealand Black/White mice. Enhanced gene expression and acceleration of renal injury", "ispublished": "pub", "full_text_status": "restricted", "note": "\u00a9 1989 American Association of Immunologists. \n\nReceived for publication July 24, 1989. Accepted for publication September 8, 1989. \n\nWe would like to thank Dr. Anthony M. Jevnikar and Dr. Charles B. Carpenter for helpful comments on the manuscript. We would also like to thank Dr. Ivan Otterness for his generous gift of IL-1\u03b1. \n\nSupported by NIH Grants DK-36149 (V.E.K.), DK-40839 (V.E.K.), CA-48626 (V.E.K.), and AI-07918 (D.C.B.), and the Jules and Gwenn Knapp Charitable Foundation. R.P.W. is the recipient of a grant from the Swiss National Science Foundation.", "abstract": "TNF and IL-1 are potent immunologic and inflammatory cytokines. We have previously reported increased levels of mRNA for TNF alpha and IL-1 beta in MRL-lpr mice with lupus nephritis. To determine whether the increased levels of TNF and IL-1 mRNA are a more general feature of mice with lupus nephritis we studied cytokine gene expression in female NZB x NZW F1 (NZB/W) mice by Northern blot analysis. Enhanced steady state levels of mRNA for TNF alpha and IL-1 beta, but not IL-1 alpha, were detected in the renal cortices of animals with lupus nephritis. To determine whether administration of TNF or IL-1 would accelerate renal injury and mortality, we injected murine rTNF alpha or rIL-1 alpha i.p. into female NZB/W or C3H/FeJ mice at two doses, 2.0 micrograms or 0.2 micrograms, three times weekly for 2 or 4 mo beginning at 2 or 4 mo of age. Administration of the lower dose of each cytokine accelerated renal disease and mortality rate when treatment was initiated at 4 mo of age. At the higher dose, neither cytokine promoted disease. Treatment administered from 2-4 mo of age did not accelerate renal disease. This observation suggests that in order to cause renal injury, these cytokines must interact with other pathologic features present in these animals after 4 mo of age. These findings support the hypothesis that TNF and IL-1 can contribute to nephritis in murine models of lupus. Taken together with previously published data, we propose that TNF and IL-1 have differential dose effects on renal disease. The dose of TNF and IL-1 and the stage of disease activity dictate the pathogenic action of these cytokines.", "date": "1989-12-01", "date_type": "published", "publication": "Journal of Immunology", "volume": "143", "number": "11", "publisher": "American Association of Immunologists", "pagerange": "3470-3475", "id_number": "CaltechAUTHORS:20170303-151541749", "issn": "0022-1767", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170303-151541749", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "DK-36149" }, { "agency": "NIH", "grant_number": "DK-40839" }, { "agency": "NIH", "grant_number": "CA-48626" }, { "agency": "NIH", "grant_number": "AI-07918" }, { "agency": "Jules and Gwenn Knapp Charitable Foundation" }, { "agency": "Swiss National Science Foundation (SNSF)" } ] }, "resource_type": "article", "pub_year": "1989", "author_list": "Brennan, Daniel C.; Yui, Mary A.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/ne6zw-93x17", "eprint_id": 74739, "eprint_status": "archive", "datestamp": "2023-08-19 21:17:42", "lastmod": "2023-10-24 22:53:45", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Wuthrich-R-P", "name": { "family": "Wuthrich", "given": "Rudolf P." } }, { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary A." }, "orcid": "0000-0002-3136-2181" }, { "id": "Mazoujian-G", "name": { "family": "Mazoujian", "given": "Gwen" } }, { "id": "Nabavi-N", "name": { "family": "Nabavi", "given": "Nasrin" } }, { "id": "Glimcher-L-H", "name": { "family": "Glimcher", "given": "Laurie H." } }, { "id": "Kelley-V-E", "name": { "family": "Kelley", "given": "Vicki E." } } ] }, "title": "Enhanced MHC class II expression in renal proximal tubules precedes loss of renal function in MRL/lpr mice with lupus nephritis", "ispublished": "pub", "full_text_status": "restricted", "note": "\u00a9 1989 American Association of Pathologists. \n\nAccepted for publication August 16, 1988. \n\nSupported by NIH grants DK-36149 (V.E.K.) and Al-19414 (G.M.), by the Pennsylvania and the Massachusetts Lupus Foundations, and the Jules and Gwen Knapp Charitable Foundation. Rudolf P. Wuthrich is the recipient of a grant from the Swiss National Science Foundation.", "abstract": "Enhanced MHC class II (Ia) antigen expression is a common feature of autoimmunity. The authors investigated the occurrence of renal Ia expression in MRL/MpJ-lpr/lpr (MRL/lpr) mice with lupus nephritis. By immunoperoxidase staining, normal C3H/FeJ and the congenic strain MRL/MpJ-+/+ express Ia in mononuclear cells in the interstitium only, whereas MRL/lpr with nephritis have abundant Ia expression in proximal tubules (PT), mainly towards the basolateral membrane, and in the characteristic perivascular infiltrates. To a lesser extent, enhanced Ia expression is also observed in the interstitium and in the glomerular mesangium. By Northern blot analysis, the increase in Ia surface determinants correlates with an increased steady-state level of class II mRNA for both I-A and I-E. Ia expression on PT starts focally at around 2-months of age, often in proximity to vascular infiltrates, and precedes overt glomerulo-nephritis and proteinuria. Enhanced class II expression is not restricted to the kidney. MRL/lpr have also increased interstitial class II antigen expression in liver, lung, and spleen compared with normal C3H/FeJ mice. Thus, MRL/lpr mice have enhanced systemic Ia expression, but Ia antigen expression is particularly prominent in PT and may play a key role in the initiation and progression of lupus nephritis.", "date": "1989-01", "date_type": "published", "publication": "American Journal of Pathology", "volume": "134", "number": "1", "publisher": "Elsevier", "pagerange": "45-51", "id_number": "CaltechAUTHORS:20170303-154834967", "issn": "0002-9440", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170303-154834967", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "DK-36149" }, { "agency": "NIH", "grant_number": "Al-19414" }, { "agency": "Pennsylvania Lupus Foundation" }, { "agency": "Massachusetts Lupus Foundation" }, { "agency": "Jules and Gwen Knapp Charitable Foundation" }, { "agency": "Swiss National Science Foundation (SNSF)" } ] }, "pmcid": "PMC1879559", "resource_type": "article", "pub_year": "1989", "author_list": "Wuthrich, Rudolf P.; Yui, Mary A.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/dysg0-c4620", "eprint_id": 74741, "eprint_status": "archive", "datestamp": "2023-08-19 21:00:46", "lastmod": "2023-10-24 22:53:55", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Boswell-J-M", "name": { "family": "Boswell", "given": "Jaquie M." } }, { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary A." }, "orcid": "0000-0002-3136-2181" }, { "id": "Burt-D-W", "name": { "family": "Burt", "given": "David W." } }, { "id": "Rubin-Kelley-V-E", "name": { "family": "Kelley", "given": "Vicki E." } } ] }, "title": "Increased tumor necrosis factor and IL-1 beta gene expression in the kidneys of mice with lupus nephritis", "ispublished": "pub", "full_text_status": "restricted", "note": "\u00a9 1988 American Association of Immunologists. \n\nReceived for publication January 19, 1988. Accepted for publication July 26, 1988. \n\nThis work was supported by Grant DK-36149 from the National Institutes of Health. and the Pennsylvania and Massachusetts Lupus Foundations. \n\nWe thank Drs. Charles B. Carpenter, Stefan Endres, and Rudolf Wuthrich for helpful comments on the manuscript. We also wish to thank Chu Chang for excellent technical assistance, and Corinne Kennedy for careful secretarial assistance. \n\nThe costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.", "abstract": "Because TNF and IL-1 can initiate immunologic and inflammatory events alone or synergistically, a local increase in the levels of one or both of these cytokines in vivo may cause irreparable tissue damage. The purpose of this study was to evaluate local TNF and IL-1 beta gene expression in vivo in the kidneys of MRL-Ipr mice with autoimmune lupus nephritis. TNF mRNA was detected in the renal cortex of MRL-Ipr mice but was not present in the cortex of normal congenic MRL-++ or C3H/FeJ mice. MRL-Ipr mice with lupus nephritis expressed higher amounts of TNF mRNA compared with MRL-Ipr mice prior to disease. In addition, freshly isolated, unstimulated glomeruli from MRL-Ipr mice with nephritis were found to secrete detectable levels of TNF, whereas glomeruli from MRL-++ mice did not. IL-1 beta mRNA, present in the renal cortex of C3H/FeJ, MRL-++, and young MRL-Ipr mice with normal kidneys, was also more abundantly expressed in MRL-Ipr mice with nephritis. Cultured macrophages from glomeruli of mice with nephritis were found to express TNF and IL-1 beta mRNA and product. These macrophages are prominent only in MRL-Ipr mice with renal disease and are the likely source of increased gene expression for both cytokines.", "date": "1988-11-01", "date_type": "published", "publication": "Journal of Immunology", "volume": "141", "number": "9", "publisher": "American Association of Immunologists", "pagerange": "3050-3054", "id_number": "CaltechAUTHORS:20170303-160017956", "issn": "0022-1767", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170303-160017956", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "DK-36149" }, { "agency": "Pennsylvania Lupus Foundation" }, { "agency": "Massachusetts Lupus Foundation" } ] }, "resource_type": "article", "pub_year": "1988", "author_list": "Boswell, Jaquie M.; Yui, Mary A.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/75r87-d5v67", "eprint_id": 74744, "eprint_status": "archive", "datestamp": "2023-08-19 20:44:23", "lastmod": "2023-10-24 22:54:03", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Boswell-J-M", "name": { "family": "Boswell", "given": "Jaquie M." } }, { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary A." }, "orcid": "0000-0002-3136-2181" }, { "id": "Endres-S", "name": { "family": "Endres", "given": "Stefan" } }, { "id": "Burt-D-W", "name": { "family": "Burt", "given": "David W." } }, { "id": "Rubin-Kelley-V-E", "name": { "family": "Kelley", "given": "Vicki E." } } ] }, "title": "Novel and enhanced IL-1 gene expression in autoimmune mice with lupus", "ispublished": "pub", "full_text_status": "restricted", "note": "\u00a9 1988 American Association of Immunologists. \n\nReceived for publication January 19. 1988. Accepted for publication April 8, 1988. \n\nThis work was supported by the National Institutes of Health Grant AM 36149 and the Pennsylvania Lupus Foundation. \n\nWe thank Drs. Terry B. Strom and Charles B. Carpenter for helpful suggestions and reviewing this manuscript. We also thank Corinne Kennedy for her careful secretarial assistance. \n\nThe costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.", "abstract": "IL-1 is a pleiotropic factor encoded for by at least two genes, alpha and beta, and capable of eliciting a broad set of immunologic and inflammatory events. MRL/MP-lpr (MRL-lpr) mice are an appealing model for studies of renal injury inasmuch as disease in this strain is spontaneous, rapid, predictable, and regulated by the lpr gene. Infiltration of macrophages and the proliferation of the glomerular mesangial cells are prominent features of renal disease. Because both mesangial cells and macrophages can synthesize IL-1, the purpose of this study was to determine whether enhanced IL-1 gene expression is associated with lupus nephritis in the MRL-lpr mouse model. Glomerular macrophages, abundant in the kidneys of MRL-lpr mice but rarely present in the kidney of congenic MRL/MP-++(MRL-++) mice, were isolated and cultured and found to express a 10-fold increase in both IL-1 alpha and IL-1 beta mRNA transcripts as compared with MRL-++ and MRL-lpr mesangial cells. IL-1 alpha was not detected in the total RNA extracted from freshly excised kidney, whereas IL-1 beta transcripts were detected in both the renal cortex of MRL-lpr as well as MRL-++ animals. A previously undetected truncated 1200 nucleotide IL-1 beta transcript together with the conventional 1600 nucleotide IL-1 beta transcript was found in kidneys from MRL-lpr and was abundantly expressed in glomeruli of MRL-lpr mice with lupus nephritis. Isolated glomeruli from MRL-lpr mice with nephritis produce IL-1, whereas in normal glomeruli from MRL-++ and C3H/FeJ mice this cytokine was not detected. Glomerular macrophages and mesangial cells cultured from MRL-lpr mice with nephritis both secrete IL-1. These studies indicate that IL-1 beta gene expression and IL-1 protein are increased in the kidneys of autoimmune mice with lupus nephritis and is generated, at least in part, by glomerular macrophages. We speculate that an alteration in IL-1 beta gene expression may be responsible for causing a cascade of events leading to acute and chronic renal injury.", "date": "1988-07-01", "date_type": "published", "publication": "Journal of Immunology", "volume": "141", "number": "1", "publisher": "American Association of Immunologists", "pagerange": "118-124", "id_number": "CaltechAUTHORS:20170303-162003195", "issn": "0022-1767", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170303-162003195", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "AM 36149" }, { "agency": "Pennsylvania Lupus Foundation" } ] }, "resource_type": "article", "pub_year": "1988", "author_list": "Boswell, Jaquie M.; Yui, Mary A.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/ve6cx-7mc33", "eprint_id": 75373, "eprint_status": "archive", "datestamp": "2023-08-19 19:10:32", "lastmod": "2023-10-25 14:59:40", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Kaattari-S-L", "name": { "family": "Kaattari", "given": "Stephen L." } }, { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary A." }, "orcid": "0000-0002-3136-2181" } ] }, "title": "Polyclonal activation of salmonid B lymphocytes", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 1987 Elsevier.", "abstract": "The process of invitro polyclonal activation of coho salmon (Oncorhynchuskisutch) lymphocytes was examined with respect to the induction of mitogenesis, total immunoglobulin production, and the production of specific antibodies or plaque forming cells. These studies demonstrate that antigen specific stimulation of antibody production is not linked to mitogenic activity, or total immunoglobulin production, while the polyclonal activation of specific antibody production is closely linked to these functions. Stimulation of immunoglobulin production by phytohemagglutinin suggests that this mitogen may not be limited to T cell activation in salmonids or, alternatively, it may induce the production of lymphokines capable of polyclonally activating B cells. Further, fetal calf serum was found to cause production of large amounts of immunoglobulin in without antigenic stimulation.", "date": "1987", "date_type": "published", "publication": "Developmental and Comparative Immunology", "volume": "11", "number": "1", "publisher": "Elsevier", "pagerange": "155-165", "id_number": "CaltechAUTHORS:20170324-082256530", "issn": "0145-305X", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170324-082256530", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1016/0145-305X(87)90017-6", "resource_type": "article", "pub_year": "1987", "author_list": "Kaattari, Stephen L. and Yui, Mary A." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/x5k7x-cnr22", "eprint_id": 75371, "eprint_status": "archive", "datestamp": "2023-08-19 19:10:25", "lastmod": "2023-10-25 14:59:35", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary A." }, "orcid": "0000-0002-3136-2181" }, { "id": "Kaattari-S-L", "name": { "family": "Kaattari", "given": "Stephen L." } } ] }, "title": "Vibrioanguillarum antigen stimulates mitogenesis and polyclonal activation of salmonid lymphocytes", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 1987 Elsevier.", "abstract": "An antigen preparation of Vibrioanguillarum, a salmonid pathogen, acts as a potent invitro mitogenic stimulator of splenic and pronephric (anterior kidney) lymphocytes from coho salmon (Oncorhynchuskisutch), chinook salmon (O.tshawytscha) and rainbow trout (Salmogairdneri). This antigen (VA) is comparable in its mitogenic activity to Concanavalin A (Con A), Escherichiacoli lipopolysaccharide (LPS), and phytohemagglutinin (PHA). VA gives peak mitogenic responses in coho five days after initiation of cell culture. VA also appears to be a nonspecific polyclonal activator as determined by the generation of plaque forming cells to trinitrophenyl (TNP) and fluorescein (FI) haptenic determinants. Chemical characterization is limited, but it appears that Vibrio LPS could be responsible for these activities.", "date": "1987", "date_type": "published", "publication": "Developmental and Comparative Immunology", "volume": "11", "number": "3", "publisher": "Elsevier", "pagerange": "539-549", "id_number": "CaltechAUTHORS:20170324-081103820", "issn": "0145-305X", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170324-081103820", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1016/0145-305X(87)90043-7", "resource_type": "article", "pub_year": "1987", "author_list": "Yui, Mary A. and Kaattari, Stephen L." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/m5xtk-15450", "eprint_id": 75372, "eprint_status": "archive", "datestamp": "2023-08-19 19:10:28", "lastmod": "2023-10-25 14:59:37", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Bayne-C-J", "name": { "family": "Bayne", "given": "Christopher J." } }, { "id": "Boswell-C-A", "name": { "family": "Boswell", "given": "Carl A." } }, { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary A." }, "orcid": "0000-0002-3136-2181" } ] }, "title": "Widespread antigenic cross-reactivity between plasma proteins of a gastropod, and its trematode parasite", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 1987 Elsevier.", "abstract": "Evidence obtained earlier with immunofluorescence and immunoelectron microscopy was interpreted to imply molecular mimicry of the host Biomphalariaglabrata by the parasite Schistosomamansoni. Using Western Blotting, we find that \"mimicry\" is due to widespread shared epitopes. Furthermore, at least one individual plasma protein of B. glabrata shares epitopes with the majority of plasma proteins in the mollusc. The widespread antigenic determinants may be carbohydrates. Caution is warranted when antisera, raised in mammals against heterogeneous invertebrate extracts, are used to screen for related antigenic determinants.", "date": "1987", "date_type": "published", "publication": "Developmental and Comparative Immunology", "volume": "11", "number": "2", "publisher": "Elsevier", "pagerange": "321-329", "id_number": "CaltechAUTHORS:20170324-081913330", "issn": "0145-305X", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170324-081913330", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1016/0145-305X(87)90076-0", "resource_type": "article", "pub_year": "1987", "author_list": "Bayne, Christopher J.; Boswell, Carl A.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/ny7tb-yns59", "eprint_id": 75375, "eprint_status": "archive", "datestamp": "2023-08-22 04:55:55", "lastmod": "2023-10-25 14:59:44", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Loker-E-S", "name": { "family": "Loker", "given": "Eric S." } }, { "id": "Bayne-C-J", "name": { "family": "Bayne", "given": "Christopher J." } }, { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary A." }, "orcid": "0000-0002-3136-2181" } ] }, "title": "Echinostoma paraensei: Hemocytes of Biomphalaria glabrata as targets of echinostome mediated interference with host snail resistance to Schistosoma mansoni", "ispublished": "pub", "full_text_status": "public", "keywords": "Schistosoma mansoni; Echinostoma paraensei; Trematodes; Biomphalaria glabrata; Snail; Immunoparasitology; Hemolymph; Hemocytes; Interference", "note": "\u00a9 1986 Elsevier Inc. \n\nAccepted 2 January 1986.", "abstract": "Earlier in vivo work by Lie et al. (1977) indicated that the innate resistance of the 10R2 strain of Biomphalaria glabrata to PR1 Schistosoma mansoni could be interfered with if the snails were infected previously with another trematode, Echinostoma paraensei. We have studied this interference phenomenon using in vitro methods in an attempt to understand its mechanistic basis. Hemolymph, derived from 10R2 snails infected with E. paraensei for 14\u201328 days, killed 25% of S. mansoni sporocysts in vitro, significantly less (P < 0.001) than the 90% killing rate observed with hemolymph from uninfected, control 10R2 snails. Hemolymph from the infected 10R2 snails and from schistosome susceptible M line snails did not differ significantly (P > 0.1) in their relative inability to kill S. mansoni sporocysts in vitro. The defect in sporocyst killing exhibited by echinostome infected 10R2 snails was traced to the cellular, rather than the humoral, component of the hemolymph. Preparations containing uninfected 10R2 snail hemolymph and echinostome daughter rediae exhibited significantly less (P < 0.001) killing of S. mansoni sporocysts than did controls containing only 10R2 hemolymph and S. mansoni sporocysts. Our results suggest that echinostome larvae release factors that interfere with the ability of B. glabrata hemocytes to kill S. mansoni sporocysts.", "date": "1986-08", "date_type": "published", "publication": "Experimental Parasitology", "volume": "62", "number": "1", "publisher": "Elsevier", "pagerange": "149-154", "id_number": "CaltechAUTHORS:20170324-082803941", "issn": "0014-4894", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170324-082803941", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1016/0014-4894(86)90018-4", "resource_type": "article", "pub_year": "1986", "author_list": "Loker, Eric S.; Bayne, Christopher J.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/3fekk-93f17", "eprint_id": 74754, "eprint_status": "archive", "datestamp": "2023-08-19 18:40:02", "lastmod": "2023-10-24 22:54:31", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Bayne-C-J", "name": { "family": "Bayne", "given": "C. J." } }, { "id": "Loker-E-S", "name": { "family": "Loker", "given": "E. S." } }, { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary A." }, "orcid": "0000-0002-3136-2181" } ] }, "title": "Interactions between the plasma proteins of Biomphalaria glabrata (Gastropoda) and the sporocyst tegument of Schistosoma mansoni (Trematoda)", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 1986 Cambridge University Press.", "abstract": "The tegumental surface of Schistosoma mansoni sporocysts is the site of both nutritive and immunological interactions with haemolymph cells and plasma of Biomphalaria glabrata, the schistosome intermediate host. Within minutes of being placed in host plasma, sporocysts acquire plasma antigens, and within 3 h host plasma antigens are present on the surface at near steady state. Though a wide variety of peptides is acquired, there is selection. Furthermore, some differences occur in the peptides acquired from the plasma of susceptible and resistant strains of snail. Acquired antigens are rapidly processed, and are predominantly undetectable in tegumental extracts after a few hours. In contrast, rabbit antibody on sporocysts remains in situ for at least 48 h, so under some conditions there is stable expression of certain tegumental antigenic determinants.These data, obtained using antibodies to snail plasma antigens and to sporocyst tegumental antigens, are discussed in the light of current ideas on the cellular and molecular basis of susceptibility and resistance in this host#parasite system.", "date": "1986-06", "date_type": "published", "publication": "Parasitology", "volume": "92", "number": "3", "publisher": "Cambridge University Press", "pagerange": "653-664", "id_number": "CaltechAUTHORS:20170303-165345043", "issn": "0031-1820", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170303-165345043", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1017/S0031182000065513", "resource_type": "article", "pub_year": "1986", "author_list": "Bayne, C. J.; Loker, E. S.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/b98e5-bbz03", "eprint_id": 75380, "eprint_status": "archive", "datestamp": "2023-08-19 18:40:05", "lastmod": "2023-10-25 14:59:59", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Kaattari-S-L", "name": { "family": "Kaattari", "given": "S. L." } }, { "id": "Irwin-M-J", "name": { "family": "Irwin", "given": "M. J." } }, { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "M. A." }, "orcid": "0000-0002-3136-2181" }, { "id": "Tripp-R-A", "name": { "family": "Tripp", "given": "R. A." } }, { "id": "Parkins-J-S", "name": { "family": "Parkins", "given": "J. S." } } ] }, "title": "Primary in vitro stimulation of antibody production by rainbow trout lymphocytes", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 1986 Elsevier B.V.", "abstract": "Trinitrophenylated (TNP) forms ofE. coli lipopolysaccharide (LPS) and keyhole limpet hemocyanin (KLH) were used to produce antigen specific plaque-forming cell (PFC) responses with rainbow trout (Salmo gairdneri) splenocytes from unprimed fishin vitro. The culture system that was developed is described and characterized with respect to the kinetics and dose responses for both the haptenated and unhaptenated forms of the carriers. The induction of the PFC response to TNP-LPS was inhibited with TNP-lysine. Exposure to graded levels of gamma-radiation demonstrated a low dose augmentation of the PFC response with both antigens. Antigen addition experiments reveal that both antigens appear to stimulate the same population of antibody-producing B lymphocytes.", "date": "1986-06", "date_type": "published", "publication": "Veterinary Immunology and Immunopathology", "volume": "12", "number": "1-4", "publisher": "Elsevier", "pagerange": "29-38", "id_number": "CaltechAUTHORS:20170324-085913382", "issn": "0165-2427", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170324-085913382", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1016/0165-2427(86)90107-8", "resource_type": "article", "pub_year": "1986", "author_list": "Kaattari, S. L.; Irwin, M. J.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/e7sdj-th149", "eprint_id": 74753, "eprint_status": "archive", "datestamp": "2023-08-19 17:28:26", "lastmod": "2023-10-24 22:54:29", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Bayne-C-J", "name": { "family": "Bayne", "given": "Christopher J." } }, { "id": "Boswell-C-A", "name": { "family": "Boswell", "given": "Carl A." } }, { "id": "Locker-E-S", "name": { "family": "Locker", "given": "Eric S." } }, { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary A." }, "orcid": "0000-0002-3136-2181" } ] }, "title": "Plasma components which mediate cellular defences in the gastropod mollusc Biomphalaria glabrata", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 1985 Elsevier Ltd. \n\nThis paper summarises a talk presented to the American Society of Zoologists, Division of Developmental and Comparative Immunology in Denver, CO. Dec. 1984, and is based on work published in other (cited) primary papers.", "abstract": "Blood plasmas from certain strains of Biomphalariaglabrata are known to have components which facilitate a hemocyte-effected cytotoxic response against encapsulated Schistosomamansoni sporocysts. The possible identity of the factor(s) has been investigated. Sporocysts placed in snail plasma rapidly acquire a wide variety of host plasma antigens, at least some of which are displayed on the parasite surface. Plasmas from strains of snail resistant to the parasite agglutinate fixed sporocysts, while plasmas from susceptible strains fail to do so. Fixed sporocysts incubated in plasma bind selectively a subpopulation of plasma antigens; some are bound uniquely in resistant plasma. Another resembles a hemagglutinin from snail plasma. These and other recently acquired data are discussed in light of increasing evidence for defensive roles of multivalent lectins.", "date": "1985", "date_type": "published", "publication": "Developmental and Comparative Immunology", "volume": "9", "number": "3", "publisher": "Elsevier", "pagerange": "523-530", "id_number": "CaltechAUTHORS:20170303-165215438", "issn": "0145-305X", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170303-165215438", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1016/0145-305X(85)90015-1", "resource_type": "article", "pub_year": "1985", "author_list": "Bayne, Christopher J.; Boswell, Carl A.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/2de8y-q4y20", "eprint_id": 74751, "eprint_status": "archive", "datestamp": "2023-08-19 17:14:00", "lastmod": "2023-10-24 22:54:27", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Loker-E-S", "name": { "family": "Loker", "given": "Eric S." } }, { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary A." }, "orcid": "0000-0002-3136-2181" }, { "id": "Bayne-C-J", "name": { "family": "Bayne", "given": "Christopher J." } } ] }, "title": "Schistosoma mansoni: Agglutination of sporocysts, and formation of gels on miracidia transforming in plasma of Biomphalaria glabrata", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 1984, John Wiley and Sons. \n\nAccepted for publication 24 May 1984.", "abstract": "Cellular interactions, leading to cell-mediated cytotoxicity when Biomphalaria glabrata hemocytes encapsulate Schistosoma mansoni sporocysts, have been investigated. Rabbit antibodies (IgG), when bound to antigens on sporocyst surfaces, prevent the normal cytoadherence (CA) of hemocytes from both susceptible and resistant host snails. Since interference with CA occurs with even fixed sporocysts, the effect is not due to IgG stimulated modulation of the parasite surface. Using two antisera with some overlapping specificities, and quantitative immunofluorescent antibody technique (QIFAT), we determined the concentrations of IgG needed to place equivalent amounts of IgG on the sporocysts. At these concentrations, CA was affected differentially, implying that interference was due to the specific antigens bound, and not due simply to the presence of IgG. Also with QIFAT we determined how much F(ab')2 and IgG from anti-sporocyst serum were needed to block an equivalent amount of antigenic determinants from access by whole FITC labelled IgG. Sporocysts whose surface antigens were equally blocked were equally unadherent for hemocytes, supporting the notion that the nature of obscured antigens, and neither the Fc portion nor the larger size of intact IgG protein, was responsible for the effect on CA. These surprising results imply a role for specific antigen binding sites on snail hemocytes.", "date": "1984-11", "date_type": "published", "publication": "Experimental Parasitology", "volume": "58", "number": "1", "publisher": "John Wiley and Sons", "pagerange": "56-62", "id_number": "CaltechAUTHORS:20170303-165004725", "issn": "0014-4894", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170303-165004725", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1111/j.1365-3024.1984.tb00822.x", "resource_type": "article", "pub_year": "1984", "author_list": "Loker, Eric S.; Yui, Mary A.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/1avkg-w0t61", "eprint_id": 74747, "eprint_status": "archive", "datestamp": "2023-08-19 16:15:17", "lastmod": "2023-10-24 22:54:16", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Yui-Mary-A", "name": { "family": "Yui", "given": "Mary A." }, "orcid": "0000-0002-3136-2181" }, { "id": "Bayne-C-J", "name": { "family": "Bayne", "given": "Christopher J." } } ] }, "title": "Echinoderm Immunology: Bacterial clearance by the sea urchin, Strongylocentrotus purpuratus", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 1983 University of Chicago. \n\nReceived 11 April 1983; accepted 25 July 1983. \n\nWe thank E. S. Loker and C. A. Boswell for suggestions on the manuscript, and J. A. Longmate for assistance collecting urchins. The research was supported by grants from the Oregon State University Zoology Department Research Fund.\n\nPublished - 1541213.pdf
", "abstract": "Characteristics of bacterial clearance were investigated in the purple sea urchin, Strongylocentrotus purpuratus (Echinodermata: Echinoidea). Primary clearance kinetics were determined for three bacteria, a marine Gram negative motile rod, a marine Gram positive non-motile rod, and a Gram negative freshwater fish pathogen, Aeromonas salmonicida. Clearance kinetics differed for each of the three bacteria. Secondary clearance rates were not significantly different from primary clearance rates for any of the three bacteria, regardless of the time interval between inoculations (9-21 days), implying a probable absence of immunologic memory. During primary clearance, total coelomocyte counts declined 93% by 90 min post injection. All four coelomocyte types declined, however the relative proportions of each type changed during the six-hour sampling period. In cell-free coelomic fluid, viable counts of marine bacteria declined, with different kinetics for the two species. Viable counts in sea water controls did not change. Declines in viable counts may be due to bactericidal activity and/or agglutination, although bacterial agglutination was not observed.", "date": "1983-10", "date_type": "published", "publication": "Biological Bulletin", "volume": "165", "number": "2", "publisher": "Marine Biological Laboratory", "pagerange": "473-486", "id_number": "CaltechAUTHORS:20170303-163721060", "issn": "0006-3185", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170303-163721060", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Oregon State University" } ] }, "primary_object": { "basename": "1541213.pdf", "url": "https://authors.library.caltech.edu/records/1avkg-w0t61/files/1541213.pdf" }, "resource_type": "article", "pub_year": "1983", "author_list": "Yui, Mary A. and Bayne, Christopher J." } ]