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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,7,25]]},"abstract":"<jats:p>\n                    Aquaporin-4 (AQP4)-specific Th17 cells are thought to have a central role in neuromyelitis optica (NMO) pathogenesis. When modeling NMO, only AQP4-reactive Th17 cells from AQP4-deficient (AQP4\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    ), but not wild-type (WT) mice, caused CNS autoimmunity in recipient WT mice, indicating that a tightly regulated mechanism normally ensures tolerance to AQP4. Here, we found that pathogenic AQP4 T cell epitopes bind MHC II with exceptionally high affinity. Examination of T cell receptor (TCR) \u03b1\/\u03b2 usage revealed that AQP4-specific T cells from AQP4\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice employed a distinct TCR repertoire and exhibited clonal expansion. Selective thymic AQP4 deficiency did not fully restore AQP4-reactive T cells, demonstrating that thymic negative selection alone did not account for AQP4-specific tolerance in WT mice. Indeed, AQP4-specific Th17 cells caused paralysis in recipient WT or B cell-deficient mice, which was followed by complete recovery that was associated with apoptosis of donor T cells. However, donor AQP4-reactive T cells survived and caused persistent paralysis in recipient mice deficient in both T and B cells or mice lacking T cells only. Thus, AQP4 CNS autoimmunity was limited by T cell\u2013dependent deletion of AQP4-reactive T cells. In contrast, myelin oligodendrocyte glycoprotein (MOG)-specific T cells survived and caused sustained disease in WT mice. These findings underscore the importance of peripheral T cell deletional tolerance to AQP4, which may be relevant to understanding the balance of AQP4-reactive T cells in health and in NMO. T cell tolerance to AQP4, expressed in multiple tissues, is distinct from tolerance to MOG, an autoantigen restricted in its expression.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2306572120","type":"journal-article","created":{"date-parts":[[2023,7,18]],"date-time":"2023-07-18T13:35:13Z","timestamp":1689687313000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":27,"title":["T cell deletional tolerance restricts AQP4 but not MOG CNS autoimmunity"],"prefix":"10.1073","volume":"120","author":[{"given":"Sharon A.","family":"Sagan","sequence":"first","affiliation":[{"name":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA 94143"},{"name":"Program in Immunology, University of California, San Francisco, CA 94143"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zahra","family":"Moinfar","sequence":"additional","affiliation":[{"name":"Department of Neurology, 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