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The immunopathology in neuromyelitis optica is largely driven by autoantibodies to AQP4\n                    <jats:sup>2<\/jats:sup>\n                    . However, the T cell response that is required for the generation of these anti-AQP4 antibodies is not well understood. Here we show that B cells endogenously express AQP4 in response to activation with anti-CD40 and IL-21 and are able to present their endogenous AQP4 to T cells with an AQP4-specific T cell receptor (TCR). A population of thymic B cells emulates a CD40-stimulated B cell transcriptome, including AQP4 (in mice and humans), and efficiently purges the thymic TCR repertoire of AQP4-reactive clones. Genetic ablation of\n                    <jats:italic>Aqp4<\/jats:italic>\n                    in B cells rescues AQP4-specific TCRs despite sufficient expression of AQP4 in medullary thymic epithelial cells, and B-cell-conditional AQP4-deficient mice are fully competent to raise AQP4-specific antibodies in productive germinal-centre responses. Thus, the negative selection of AQP4-specific thymocytes is dependent on the expression and presentation of AQP4 by thymic B cells. As AQP4 is expressed in B cells in a CD40-dependent (but not AIRE-dependent) manner, we propose that thymic B cells might tolerize against a group of germinal-centre-associated antigens, including disease-relevant autoantigens such as AQP4.\n                  <\/jats:p>","DOI":"10.1038\/s41586-024-07079-8","type":"journal-article","created":{"date-parts":[[2024,2,21]],"date-time":"2024-02-21T12:02:21Z","timestamp":1708516941000},"page":"407-415","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":78,"title":["B cells orchestrate tolerance to the neuromyelitis optica autoantigen AQP4"],"prefix":"10.1038","volume":"627","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3256-5298","authenticated-orcid":false,"given":"Ali 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