Antigen-specific B cells cross-present citrullinated proteins to activate CD8 T cells in rheumatoid arthritis 4385

Abstract Description Dysregulated autoreactive CD8 T cell responses contribute to the pathogenesis of autoimmune diseases including rheumatoid arthritis (RA), a disease characterized by the development of anti-citrullinated protein antibodies (ACPA). We previously identified clonally expanded cytotoxic granzyme B+ CD8 T cells that target citrullinated antigens, and demonstrated that they traffic between the blood and synovium in RA; however, the underlying mechanisms by which these autoreactive CD8 T cells are activated to mediate RA synovial tissue destruction are unknown. Here, we demonstrate that mucosal breaks of oral bacteria could provide an antigenic source of citrullinated proteins through NETs. We identify citrullinated proteins that are recognized and endocytosed by ACPA+ B cells, and these B cells potently cross-present citrullinated proteins to activate anti-citrullinated protein specific CD8 T cells, which is dependent upon a Toll-like receptor (TLR) 4 signaling. We further demonstrate that citrullinated proteins stimulate B cells to secrete chemokines that attract cytotoxic CD8 T cells to form B-T cell aggregates, thereby facilitating antigen presentation to CD8 T cells in RA blood and synovium. Together, these findings suggest that antigen-specific B cells act as professional antigen-presenting cells that provide help to the activation of anti-citrullinated protein specific CD8 T cells to mediate their cytotoxicity that mediates synovitis and joint destruction in RA. Funding Sources This study was supported by NIH R01 AR078268; R01 AR063676; U19 AI110491. Topic Categories Basic Autoimmunity (BA)