B cells orchestrate tolerance to the neuromyelitis optica autoantigen AQP4

• 成果类型: Article
• 署名作者: Afzali, Ali Maisam; Nirschl, Lucy; Sie, Christopher; Pfaller, Monika; Ulianov, Oleksii; Hassler, Tobias; Federle, Christine; Petrozziello, Elisabetta; Kalluri, Sudhakar Reddy; Chen, Hsin Hsiang; Tyystjaervi, Sofia; Muschaweckh, Andreas; Lammens, Katja; Delbridge, Claire; Buettner, Andreas; Steiger, Katja; Seyhan, Goenuel; Ottersen, Ole Petter; OEllinger, Rupert; Rad, Roland; Jarosch, Sebastian; Straub, Adrian; Muehlbauer, Anton; Grassmann, Simon; Hemmer, Bernhard; Boettcher, Jan P.; Wagner, Ingrid; Kreutzfeldt, Mario; Merkler, Doron; Pardas, Irene Bonafonte; Schmidt Supprian, Marc; Buchholz, Veit R.; Heink, Sylvia; Busch, Dirk H.; Klein, Ludger; Korn, Thomas
• 署名单位: Technical University of Munich; Technical University of Munich; University of Munich; University of Munich; University of Munich; Technical University of Munich; Technical University of Munich; University of Rostock; Technical University of Munich; University of Oslo; Technical University of Munich; Technical University of Munich; Memorial Sloan Kettering Cancer Center; Technical University of Munich; University of Geneva; German Center for Infection Research
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5389
• DOI: 10.1038/s41586-024-07079-8
• 发表日期: 2024-03-14
• 页码: 407-+
• 关键词: mhc class-ii; t-cells; dendritic cells; self-antigens; aquaporin 4; expression; thymus; repertoire; generation; population

摘要

Neuromyelitis optica is a paradigmatic autoimmune disease of the central nervous system, in which the water-channel protein AQP4 is the target antigen(1). The immunopathology in neuromyelitis optica is largely driven by autoantibodies to AQP4(2). 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 Aqp4 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.