title: Tolerance checkpoint bypass permits emergence of pathogenic T cells to neuromyelitis optica autoantigen aquaporin-4.
abstract: 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.
authors.affiliation: Department of Neurology, University of California, San Francisco, CA 94143.|Program in Immunology, University of California, San Francisco, CA 94143.
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Sagan
authors.affiliation: Department of Neurology, University of California, San Francisco, CA 94143.|Program in Immunology, University of California, San Francisco, CA 94143.
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Winger
authors.affiliation: Department of Neurology, University of California, San Francisco, CA 94143.
authors.forename: Andrés
authors.initials: A
authors.lastname: Cruz-Herranz
authors.affiliation: Department of Neurology, University of California, San Francisco, CA 94143.|Program in Immunology, University of California, San Francisco, CA 94143.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Nelson
authors.affiliation: Department of Neurology, University of California, San Francisco, CA 94143.|Program in Immunology, University of California, San Francisco, CA 94143.|Department of Ophthalmology, University of California, San Francisco, CA 94143.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hagberg
authors.affiliation: Program in Immunology, University of California, San Francisco, CA 94143.|Diabetes Center, University of California, San Francisco, CA 94143.
authors.forename: Corey N
authors.initials: CN
authors.lastname: Miller
authors.affiliation: Department of Neurology, University of California, San Francisco, CA 94143.|Program in Immunology, University of California, San Francisco, CA 94143.
authors.forename: Collin M
authors.initials: CM
authors.lastname: Spencer
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305.
authors.forename: Peggy P
authors.initials: PP
authors.lastname: Ho
authors.affiliation: Department of Neurology, Neuroscience Program, University of Colorado, Denver, CO 80045.|Department of Ophthalmology, University of Colorado, Denver, CO 80045.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Bennett
authors.affiliation: Department of Neurology, Johns Hopkins University, Baltimore, MD 21287.
authors.forename: Michael
authors.initials: M
authors.lastname: Levy
authors.affiliation: Department of Ophthalmology, University of California, San Francisco, CA 94143.
authors.forename: Marc H
authors.initials: MH
authors.lastname: Levin
authors.affiliation: Department of Medicine, University of California, San Francisco, CA 94143.|Department of Physiology, University of California, San Francisco, CA 94143.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Verkman
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305; zamvil@ucsf.neuroimmunol.org steinman@stanford.edu.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Steinman
authors.affiliation: Department of Neurology, University of California, San Francisco, CA 94143.
authors.forename: Ari J
authors.initials: AJ
authors.lastname: Green
authors.affiliation: Program in Immunology, University of California, San Francisco, CA 94143.|Diabetes Center, University of California, San Francisco, CA 94143.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Anderson
authors.affiliation: Department of Pathology, Stanford University, Stanford, CA 94305.
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Sobel
authors.affiliation: Department of Neurology, University of California, San Francisco, CA 94143; zamvil@ucsf.neuroimmunol.org steinman@stanford.edu.|Program in Immunology, University of California, San Francisco, CA 94143.
authors.forename: Scott S
authors.initials: SS
authors.lastname: Zamvil
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000235:genetics* / Q000378:metabolism*; D001323:Autoantibodies / Q000276:immunology; D001324:Autoantigens / Q000737:chemistry*; D001327:Autoimmune Diseases / Q000378:metabolism; D049109:Cell Proliferation; D002490:Central Nervous System; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D007108:Immune Tolerance; D007074:Immunoglobulin G / Q000276:immunology; D007249:Inflammation; D007962:Leukocytes / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009471:Neuromyelitis Optica / Q000378:metabolism*; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000166:cytology*; D058504:Th17 Cells / Q000166:cytology
chemical_list: C496031:Aqp4 protein, mouse; D051401:Aquaporin 4; D001323:Autoantibodies; D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D007074:Immunoglobulin G
keywords: ENMO; T-cell receptor; aquaporin-4; neuromyelitis optica; tolerance