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We studied how T cell anergy is established using an anergy model in which the Zap70 hypermorphic mutant W131A is coexpressed with the OTII TCR transgene (W131AOTII). Anergy was established in the periphery, not in the thymus. Contrary to enriched tolerance gene signatures and impaired TCR signaling in mature peripheral CD4 T cells, CD4SP thymocytes exhibited normal TCR signaling in W131AOTII mice. Importantly, the maintenance of T cell anergy in W131AOTII mice required antigen presentation via MHC-II. We investigated the functional importance of the inhibitory receptor PD-1 and the E3 ubiquitin ligases Cbl-b and Grail in this model. Deletion of each did not affect expression of phenotypic markers of anergic T cells or T reg numbers. However, deletion of Cbl-b, but not Grail or PD-1, in W131AOTII mice restored T cell responsiveness and signaling. Thus, Cbl-b plays an essential role in the establishment and\/or maintenance of unresponsiveness in T cell anergy.<\/jats:p>","DOI":"10.1084\/jem.20202477","type":"journal-article","created":{"date-parts":[[2021,5,11]],"date-time":"2021-05-11T15:32:38Z","timestamp":1620747158000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":22,"title":["Cbl-b deficiency prevents functional but not phenotypic T cell anergy"],"prefix":"10.1084","volume":"218","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0488-5590","authenticated-orcid":true,"given":"Trang T.T.","family":"Nguyen","sequence":"first","affiliation":[{"name":"Russell\/Engleman Rheumatology Research Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1593-9171","authenticated-orcid":true,"given":"Zhi-En","family":"Wang","sequence":"additional","affiliation":[{"name":"2Department of Medicine, University of California, San Francisco, San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2392-3353","authenticated-orcid":true,"given":"Lin","family":"Shen","sequence":"additional","affiliation":[{"name":"Russell\/Engleman Rheumatology Research Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8232-7837","authenticated-orcid":true,"given":"Andrew","family":"Schroeder","sequence":"additional","affiliation":[{"name":"3Division of Transplant Surgery, Department of Surgery, University of California, San Francisco, San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2520-7852","authenticated-orcid":true,"given":"Walter","family":"Eckalbar","sequence":"additional","affiliation":[{"name":"2Department of Medicine, University of California, San Francisco, San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2414-9024","authenticated-orcid":true,"given":"Arthur","family":"Weiss","sequence":"additional","affiliation":[{"name":"Russell\/Engleman Rheumatology Research Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 1"},{"name":"4Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2021,5,11]]},"reference":[{"key":"2023072804505427400_bib1","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1016\/S1074-7613(03)00084-0","article-title":"GRAIL: an E3 ubiquitin ligase that inhibits cytokine gene transcription is expressed in anergic CD4+ T cells","volume":"18","author":"Anandasabapathy","year":"2003","journal-title":"Immunity."},{"key":"2023072804505427400_bib2","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1038\/35003228","article-title":"Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b","volume":"403","author":"Bachmaier","year":"2000","journal-title":"Nature."},{"key":"2023072804505427400_bib3","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the False Discovery Rate - a Practical and Powerful Approach to Multiple Testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J. 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