| Autor: |
Sagan SA; Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA 94143.; Program in Immunology, University of California, San Francisco, CA 94143., Moinfar Z; Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA 94143.; Program in Immunology, University of California, San Francisco, CA 94143., Moseley CE; Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA 94143.; Program in Immunology, University of California, San Francisco, CA 94143., Dandekar R; Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA 94143., Spencer CM; Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA 94143.; Program in Immunology, University of California, San Francisco, CA 94143., Verkman AS; Department of Medicine, University of California, San Francisco, CA 94143.; Department of Physiology, University of California, San Francisco, CA 94143., Ottersen OP; Division of Anatomy, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo NO-0316, Norway., Sobel RA; Department of Pathology, Stanford University School of Medicine, Palo Alto VA Health Care System, Palo Alto, CA 94305., Sidney J; Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA 92037., Sette A; Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA 92037.; Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California, San Diego, La Jolla, CA 92093., Anderson MS; Program in Immunology, University of California, San Francisco, CA 94143.; Diabetes Center, University of California, San Francisco, CA 94143., Steinman L; Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305., Wilson MR; Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA 94143., Sabatino JJ Jr; Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA 94143., Zamvil SS; Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA 94143.; Program in Immunology, University of California, San Francisco, CA 94143. |
| Abstrakt: |
Aquaporin-4 (AQP4)-specific Th17 cells are thought to have a central role in neuromyelitis optica (NMO) pathogenesis. When modeling NMO, only AQP4-reactive Th17 cells from AQP4-deficient (AQP4 -/- ), but not wild-type (WT) mice, caused CNS autoimmunity in recipient WT mice, indicating that a tightly regulated mechanism normally ensures tolerance to AQP4. Here, we found that pathogenic AQP4 T cell epitopes bind MHC II with exceptionally high affinity. Examination of T cell receptor (TCR) α/β usage revealed that AQP4-specific T cells from AQP4 -/- mice employed a distinct TCR repertoire and exhibited clonal expansion. Selective thymic AQP4 deficiency did not fully restore AQP4-reactive T cells, demonstrating that thymic negative selection alone did not account for AQP4-specific tolerance in WT mice. Indeed, AQP4-specific Th17 cells caused paralysis in recipient WT or B cell-deficient mice, which was followed by complete recovery that was associated with apoptosis of donor T cells. However, donor AQP4-reactive T cells survived and caused persistent paralysis in recipient mice deficient in both T and B cells or mice lacking T cells only. Thus, AQP4 CNS autoimmunity was limited by T cell-dependent deletion of AQP4-reactive T cells. In contrast, myelin oligodendrocyte glycoprotein (MOG)-specific T cells survived and caused sustained disease in WT mice. These findings underscore the importance of peripheral T cell deletional tolerance to AQP4, which may be relevant to understanding the balance of AQP4-reactive T cells in health and in NMO. T cell tolerance to AQP4, expressed in multiple tissues, is distinct from tolerance to MOG, an autoantigen restricted in its expression. |
