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This process is finely regulated through the tuning of positive and negative regulators in thymocytes. The Family with sequence similarity 49 member B (Fam49b) protein is a newly discovered negative regulator of TCR signaling that has been shown to suppress Rac-1 activity in vitro in cultured T cell lines. However, the contribution of Fam49b to the thymic development of T cells is unknown. To investigate this important issue, we generated a novel mouse line deficient in Fam49b (Fam49b-KO). We observed that Fam49b-KO double positive (DP) thymocytes underwent excessive negative selection, whereas the positive selection stage was unaffected. Fam49b deficiency impaired the survival of single positive thymocytes and peripheral T cells. This altered development process resulted in significant reductions in CD4 and CD8 single-positive thymocytes as well as peripheral T cells. Interestingly, a large proportion of the TCR\u03b3\u03b4\n                    <jats:sup>+<\/jats:sup>\n                    and CD8\u03b1\u03b1\n                    <jats:sup>+<\/jats:sup>\n                    TCR\u03b1\u03b2\n                    <jats:sup>+<\/jats:sup>\n                    gut intraepithelial T lymphocytes were absent in Fam49b-KO mice. Our results demonstrate that Fam49b dampens thymocytes TCR signaling in order to escape negative selection during development, uncovering the function of Fam49b as a critical regulator of the selection process to ensure normal thymocyte development and peripheral T cells survival.\n                  <\/jats:p>","DOI":"10.7554\/elife.76940","type":"journal-article","created":{"date-parts":[[2024,7,17]],"date-time":"2024-07-17T02:15:07Z","timestamp":1721182507000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.76940","source":"Crossref","is-referenced-by-count":3,"title":["Fam49b dampens TCR signal strength to regulate survival of positively selected thymocytes and peripheral T cells"],"prefix":"10.7554","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4968-8304","authenticated-orcid":true,"given":"Chan-Su","family":"Park","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00za53h95","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of 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