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Significance Neuromyelitis optica (NMO) is a CNS autoimmune demyelinating disease involving aquaporin-4 (AQP4)-specific IgG1, a T-cell–dependent antibody subclass. The role of T cells in NMO is unclear. We evaluated AQP4-specific T cells in WT and AQP4−/− mice. AQP4 epitopes identified in WT mice were not pathogenic. AQP4 peptide (p) 135–153 and p201–220 elicited robust T-cell responses in AQP4−/− but not WT, mice. T-cell receptor repertoire utilization for these determinants in AQP4−/− mice was unique. Donor AQP4−/− p135–153- or p201–220-specific Th17 cells entered the CNS of recipient WT mice and induced CNS autoimmunity. Our findings indicate pathogenic AQP4-specific T cells are normally restrained by central tolerance, which could be relevant to understanding the origin of pathogenic T cells in NMO.

Tolerance checkpoint bypass permits emergence of pathogenic T cells to neuromyelitis optica autoantigen aquaporin-4