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Fundamental to these distinct functions is the ligand specificity of the unique antigen receptor expressed on each mature T cell (TCR), which endows lymphocytes with the ability to behave in a cell-autonomous, disease context\u2013specific manner. Clone-specific behavioral properties are initially established during T cell development when thymocytes use TCR recognition of major histocompatibility complex (MHC) and MHC-like ligands to instruct survival versus death and to differentiate into a plethora of inflammatory and regulatory T cell lineages. Here, we review the ligand specificity of the preselection thymocyte repertoire and argue that developmental stage\u2013specific alterations in TCR signaling control cross-reactivity and foreign versus self-specificity of T cell sublineages.<\/jats:p>","DOI":"10.1084\/jem.20230897","type":"journal-article","created":{"date-parts":[[2024,7,10]],"date-time":"2024-07-10T02:20:51Z","timestamp":1720578051000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":18,"title":["The partitioning of TCR repertoires by thymic selection"],"prefix":"10.1084","volume":"221","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9074-6847","authenticated-orcid":true,"given":"Wan-Lin","family":"Lo","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03r0ha626","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Utah School of Medicine 1 Division of Microbiology and Immunology, Department of Pathology, , Salt Lake City, UT,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5423-2542","authenticated-orcid":true,"given":"Eric S.","family":"Huseby","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0464eyp60","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Massachusetts Chan Medical School 2 Department of Pathology, , Worcester, MA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2024,8,21]]},"reference":[{"key":"2025042817411581500_bib1","doi-asserted-by":"publisher","first-page":"1503","DOI":"10.1084\/jem.186.9.1503","article-title":"Specific activation of the cysteine protease CPP32 during the negative selection of T cells in the thymus","volume":"186","author":"Alam","year":"1997","journal-title":"J. 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