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How these different fates are achieved during development remains poorly understood. We now document that deletion and differentiation are agonist-signaled at different times during thymic selection and that T\n                    <jats:sub>reg<\/jats:sub>\n                    and T\n                    <jats:sub>eff<\/jats:sub>\n                    cells both arise after clonal deletion as alternative lineage fates of agonist-signaled CD4\n                    <jats:sup>+<\/jats:sup>\n                    CD25\n                    <jats:sup>+<\/jats:sup>\n                    precursors. Disruption of agonist signaling induces CD4\n                    <jats:sup>+<\/jats:sup>\n                    CD25\n                    <jats:sup>+<\/jats:sup>\n                    precursors to initiate Foxp3 expression and become T\n                    <jats:sub>reg<\/jats:sub>\n                    cells, whereas persistent agonist signaling induces CD4\n                    <jats:sup>+<\/jats:sup>\n                    CD25\n                    <jats:sup>+<\/jats:sup>\n                    precursors to become IL-2\n                    <jats:sup>+<\/jats:sup>\n                    T\n                    <jats:sub>eff<\/jats:sub>\n                    cells. Notably, we discovered that transforming growth factor-\u03b2 induces Foxp3 expression and promotes T\n                    <jats:sub>reg<\/jats:sub>\n                    cell development by disrupting weaker agonist signals and that Foxp3 expression is not induced by IL-2 except under non-physiological in vivo conditions. Thus, TCR signaling disruption versus persistence is a general mechanism of lineage fate determination in the thymus that directs development of agonist-signaled autoreactive thymocytes.\n                  <\/jats:p>","DOI":"10.1038\/s41590-023-01469-2","type":"journal-article","created":{"date-parts":[[2023,3,23]],"date-time":"2023-03-23T13:03:14Z","timestamp":1679576594000},"page":"637-651","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":55,"title":["How autoreactive thymocytes differentiate into regulatory versus effector CD4+ T cells after avoiding clonal deletion"],"prefix":"10.1038","volume":"24","author":[{"given":"Xuguang","family":"Tai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2662-0964","authenticated-orcid":false,"given":"Alyssa","family":"Indart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirelle","family":"Rojano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolai","family":"Apenes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tejas","family":"Kadakia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Craveiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amala","family":"Alag","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth","family":"Etzensperger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed Elsherif","family":"Badr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flora","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongmei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Mu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terry","family":"Guinter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5746-0073","authenticated-orcid":false,"given":"Assiatu","family":"Crossman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larry","family":"Granger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Sharrow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6626-0898","authenticated-orcid":false,"given":"Xuyu","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6780-5108","authenticated-orcid":false,"given":"Alfred","family":"Singer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,3,23]]},"reference":[{"key":"1469_CR1","doi-asserted-by":"publisher","first-page":"788","DOI":"10.1038\/nri2416","volume":"8","author":"A Singer","year":"2008","unstructured":"Singer, A., Adoro, S. & Park, J. 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