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Consequently, it has been challenging to unmask redundant functions of the NR4A family in other immune cells. Here we use a competitive bone marrow chimera strategy, coupled with conditional genetic tools, to rescue Treg homeostasis and unmask such functions. Unexpectedly, chimeras harboring\n                    <jats:italic>\n                      Nr4a1\n                      <jats:sup>\u2013\/\u2013<\/jats:sup>\n                      Nr4a3\n                      <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    (double-knockout, DKO) bone marrow developed autoantibodies and a systemic inflammatory disease despite a replete Treg compartment of largely WT origin. This disease differs qualitatively from that seen with Treg deficiency and is B cell extrinsic. Negative selection of DKO thymocytes is profoundly impaired in a cell-intrinsic manner. Consistent with escape of self-reactive T cells into the periphery, DKO T cells with functional, phenotypic, and transcriptional features of anergy accumulated in chimeric mice. Nevertheless, we observed upregulation of genes encoding inflammatory mediators in anergic DKO T cells, and DKO T cells exhibited enhanced capacity for IL-2 production. These studies reveal cell-intrinsic roles for the NR4A family in both central and peripheral T cell tolerance and demonstrate that each is essential to preserve immune homeostasis.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.151005","type":"journal-article","created":{"date-parts":[[2021,8,3]],"date-time":"2021-08-03T12:00:48Z","timestamp":1627992048000},"source":"Crossref","is-referenced-by-count":39,"title":["NR4A family members regulate T cell tolerance to preserve immune homeostasis and suppress autoimmunity"],"prefix":"10.1172","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6968-5712","authenticated-orcid":true,"given":"Ryosuke","family":"Hiwa","sequence":"first","affiliation":[{"name":"Rosalind Russell and Ephraim P. 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