dc.date.accessioned | 2024-02-14T18:01:58Z | |
dc.date.available | 2024-02-14T18:01:58Z | |
dc.date.created | 2023-09-21T10:41:44Z | |
dc.date.issued | 2023 | |
dc.identifier.citation | Sagan, Sharon A. Moinfar, Zahra Moseley, Carson E. Dandekar, Ravi Spencer, Collin M. Verkman, Alan S. Ottersen, Ole Petter Sobel, Raymond A. Sidney, John Sette, Alessandro Anderson, Mark S. Steinman, Lawrence Wilson, Michael R. Sabatino, Joseph J. Zamvil, Scott S. . T cell deletional tolerance restricts AQP4 but not MOG CNS autoimmunity. Proceedings of the National Academy of Sciences of the United States of America. 2023, 120(30) | |
dc.identifier.uri | http://hdl.handle.net/10852/108059 | |
dc.description.abstract | 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. | |
dc.language | EN | |
dc.publisher | The National Academy of Sciences | |
dc.rights | Attribution-NonCommercial-NoDerivatives 4.0 International | |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/4.0/ | |
dc.title | T cell deletional tolerance restricts AQP4 but not MOG CNS autoimmunity | |
dc.title.alternative | ENEngelskEnglishT cell deletional tolerance restricts AQP4 but not MOG CNS autoimmunity | |
dc.type | Journal article | |
dc.creator.author | Sagan, Sharon A. | |
dc.creator.author | Moinfar, Zahra | |
dc.creator.author | Moseley, Carson E. | |
dc.creator.author | Dandekar, Ravi | |
dc.creator.author | Spencer, Collin M. | |
dc.creator.author | Verkman, Alan S. | |
dc.creator.author | Ottersen, Ole Petter | |
dc.creator.author | Sobel, Raymond A. | |
dc.creator.author | Sidney, John | |
dc.creator.author | Sette, Alessandro | |
dc.creator.author | Anderson, Mark S. | |
dc.creator.author | Steinman, Lawrence | |
dc.creator.author | Wilson, Michael R. | |
dc.creator.author | Sabatino, Joseph J. | |
dc.creator.author | Zamvil, Scott S. | |
cristin.unitcode | 185,51,12,30 | |
cristin.unitname | Seksjon for anatomi | |
cristin.ispublished | true | |
cristin.fulltext | original | |
cristin.qualitycode | 2 | |
dc.identifier.cristin | 2177526 | |
dc.identifier.bibliographiccitation | info:ofi/fmt:kev:mtx:ctx&ctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Proceedings of the National Academy of Sciences of the United States of America&rft.volume=120&rft.spage=&rft.date=2023 | |
dc.identifier.jtitle | Proceedings of the National Academy of Sciences of the United States of America | |
dc.identifier.volume | 120 | |
dc.identifier.issue | 30 | |
dc.identifier.pagecount | 11 | |
dc.identifier.doi | https://doi.org/10.1073/pnas.2306572120 | |
dc.type.document | Tidsskriftartikkel | |
dc.type.peerreviewed | Peer reviewed | |
dc.source.issn | 0027-8424 | |
dc.type.version | PublishedVersion | |
cristin.articleid | e230657212 | |