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The contribution of AQP4\u2010specific T cells to the class switch recombination of pathogenic AQP4\u2010specific antibodies and the inflammation of the blood\u2013brain barrier is incompletely understood, as immunogenic naturally processed T\u2010cell epitopes of AQP4 are unknown. By immunizing <jats:italic>Aqp4<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice with full\u2010length murine AQP4 protein followed by recall with overlapping peptides, we here identify AQP4(201\u2010220) as the major immunogenic IA<jats:sup>b<\/jats:sup>\u2010restricted epitope of AQP4. We show that WT mice do not harbor AQP4(201\u2013220)\u2010specific T\u2010cell clones in their natural repertoire due to deletional tolerance. However, immunization with AQP4(201\u2013220) of <jats:italic>Rag1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice reconstituted with the mature T\u2010cell repertoire of <jats:italic>Aqp4<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice elicits an encephalomyelitic syndrome. Similarly to the T\u2010cell repertoire, the B\u2010cell repertoire of WT mice is \u201cpurged\u201d of AQP4\u2010specific B cells, and robust serum responses to AQP4 are only mounted in <jats:italic>Aqp4<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice. While AQP4(201\u2013220)\u2010specific T cells alone induce encephalomyelitis, NMO\u2010specific lesional patterns in the CNS and the retina only occur in the additional presence of anti\u2010AQP4 antibodies. Thus, failure of deletional T\u2010cell and B\u2010cell tolerance against AQP4 is a prerequisite for clinically manifest NMO.<\/jats:p>","DOI":"10.1002\/eji.201646855","type":"journal-article","created":{"date-parts":[[2017,1,6]],"date-time":"2017-01-06T03:52:49Z","timestamp":1483674769000},"page":"458-469","source":"Crossref","is-referenced-by-count":28,"title":["Deletional tolerance prevents AQP4\u2010directed autoimmunity in mice"],"prefix":"10.1002","volume":"47","author":[{"given":"Anna\u2010Lena","family":"Vogel","sequence":"first","affiliation":[{"name":"Klinikum rechts der Isar, Department of Neurology Technical University of Munich  Munich Germany"},{"name":"Klinikum rechts der Isar, Department of Experimental Neuroimmunology Technical University of Munich  Munich Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin","family":"Knier","sequence":"additional","affiliation":[{"name":"Klinikum rechts der Isar, Department of Neurology Technical 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