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The accumulation of thymocytes with such receptors is limited by negative selection or by diversion into alternative differentiation, including T regulatory cell commitment. A role for the orphan nuclear receptor NR4A3 in negative selection has been suggested, but its function in this process has never been investigated. We find that Nr4a3 transcription is upregulated in postselection double-positive thymocytes, particularly those that have received a strong selecting signal and are destined for negative selection. Indeed, we found an accumulation of cells bearing a negative selection phenotype in NR4A3-deficient mice as compared with wild-type controls, suggesting that Nr4a3 transcriptional induction is necessary to limit accumulation of self-reactive thymocytes. This is consistent with a decrease of cleaved caspase-3+\u2013signaled thymocytes and more T regulatory and CD4+Foxp3\u2212HELIOS+ cells in the NR4A3-deficient thymus. We further tested the role for NR4A3 in negative selection by reconstituting transgenic mice expressing the OVA Ag under the control of the insulin promoter with bone marrow cells from OT-I Nr4a3+\/+ or OT-I Nr4a3\u2212\/\u2212 mice. Accumulation of autoreactive CD8 thymocytes and autoimmune diabetes developed only in the absence of NR4A3. Overall, our results demonstrate an important role for NR4A3 in T cell development.<\/jats:p>","DOI":"10.4049\/jimmunol.1901228","type":"journal-article","created":{"date-parts":[[2021,7,26]],"date-time":"2021-07-26T19:00:16Z","timestamp":1627326016000},"page":"1055-1064","source":"Crossref","is-referenced-by-count":11,"title":["NR4A3 Mediates Thymic Negative Selection"],"prefix":"10.1093","volume":"207","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8446-8908","authenticated-orcid":false,"given":"Salix","family":"Boulet","sequence":"first","affiliation":[{"name":"Maisonneuve-Rosemont Hospital Research Center , Montreal, Quebec ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Livia","family":"Odagiu","sequence":"additional","affiliation":[{"name":"Maisonneuve-Rosemont Hospital Research Center , Montreal, Quebec ,","place":["Canada"]},{"name":"D\u00e9partement de Microbiologie, Infectiologie et Immunologie, Universit\u00e9 de Montr\u00e9al , Montreal, Quebec ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6246-3383","authenticated-orcid":false,"given":"Mengqi","family":"Dong","sequence":"additional","affiliation":[{"name":"Maisonneuve-Rosemont Hospital Research Center , Montreal, Quebec ,","place":["Canada"]},{"name":"D\u00e9partement de Microbiologie, Infectiologie et Immunologie, Universit\u00e9 de Montr\u00e9al , Montreal, Quebec ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8087-4810","authenticated-orcid":false,"given":"Marie-\u00c8ve","family":"Lebel","sequence":"additional","affiliation":[{"name":"Maisonneuve-Rosemont Hospital Research Center , Montreal, Quebec ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean-Fran\u00e7ois","family":"Daudelin","sequence":"additional","affiliation":[{"name":"Maisonneuve-Rosemont Hospital Research Center , Montreal, Quebec ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0951-334X","authenticated-orcid":false,"given":"Heather J","family":"Melichar","sequence":"additional","affiliation":[{"name":"Maisonneuve-Rosemont Hospital Research Center , Montreal, Quebec ,","place":["Canada"]},{"name":"D\u00e9partement de M\u00e9decine, Universit\u00e9 de Montr\u00e9al , Montreal, Quebec ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7563-1542","authenticated-orcid":false,"given":"Nathalie","family":"Labrecque","sequence":"additional","affiliation":[{"name":"Maisonneuve-Rosemont Hospital Research Center , Montreal, Quebec ,","place":["Canada"]},{"name":"D\u00e9partement de Microbiologie, Infectiologie et Immunologie, Universit\u00e9 de Montr\u00e9al , Montreal, Quebec ,","place":["Canada"]},{"name":"D\u00e9partement de M\u00e9decine, Universit\u00e9 de Montr\u00e9al , Montreal, Quebec ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2021,8,15]]},"reference":[{"key":"2025022610315321900_r1","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1038\/ni.2938","article-title":"The self-obsession of T cells: how TCR signaling thresholds affect fate \u2018decisions\u2019 and effector function","volume":"15","author":"Hogquist","year":"2014","journal-title":"Nat. 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