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标题：Tolerance checkpoint bypass permits emergence of pathogenic T cells to neuromyelitis optica autoantigen aquaporin-4
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作者：Sharon A. Sagan ; Ryan C. Winger ; Andrés Cruz-Herranz 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：51
页码：14781-14786
DOI：10.1073/pnas.1617859114
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceNeuromyelitis 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. 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-Ab-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.
关键词：neuromyelitis optica ; aquaporin-4 ; T-cell receptor ; tolerance ; ENMO