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

作者：Sagan Sharon A; Winger Ryan C; Cruz Herranz Andres; Nelson Patricia A; Hagberg Sarah; Miller Corey N; Spencer Collin M; Ho Peggy P; Bennett Jeffrey L; Levy Michael; Levin Marc H; Verkman Alan S; Steinman Lawrence^*; Green Ari J; Anderson Mark S; Sobel Raymond A; Zamvil Scott S^*

来源：Proceedings of the National Academy of Sciences of the United States of America, 2016, 113(51): 14781-14786.

DOI：10.1073/pnas.1617859114

• neuromyelitis optica
• aquaporin-4
• T-cell receptor
• tolerance
• ENMO

Aquaporin-4 (AQP4)-specific T cells are expanded in neuromyelitis optica (NMO) patients and exhibit Th17 polarization. However, their pathogenic role in CNS autoimmune inflammatory disease is unclear. Although multiple AQP4 T-cell epitopes have been identified in WT C57BL/6 mice, we observed that neither immunization with those determinants nor transfer of donor T cells targeting them caused CNS autoimmune disease in recipient mice. In contrast, robust proliferation was observed following immunization of AQP4-deficient (AQP4(-/-)) mice with AQP4 peptide (p) 135-153 or p201-220, peptides predicted to contain I-A(b)-restricted T-cell epitopes but not identified in WT mice. In comparison with WT mice, AQP4(-/-) mice used unique T-cell receptor repertoires for recognition of these two AQP4 epitopes. Donor T cells specific for either determinant from AQP4(-/-), but not WT, mice induced paralysis in recipient WT and B-cell-deficient mice. AQP4-specific Th17-polarized cells induced more severe disease than Th1-polarized cells. Clinical signs were associated with opticospinal infiltrates of T cells and monocytes. Fluorescent- labeled donor T cells were detected in CNS lesions. Visual system involvement was evident by changes in optical coherence tomography. Fine mapping of AQP4 p201-220 and p135-153 epitopes identified peptides within p201-220 but not p135-153, which induced clinical disease in 40% of WT mice by direct immunization. Our results provide a foundation to evaluate how AQP4-specific T cells contribute to AQP4-targeted CNS autoimmunity (ATCA) and suggest that pathogenic AQP4-specific T-cell responses are normally restrained by central tolerance, which may be relevant to understanding development of AQP4-reactive T cells in NMO.

• 出版日期2016-12-20