W114 - Antigen-specific B Cells Cross-Present Citrullinated Proteins to Activate CD8 T Cells in Rheumatoid Arthritis

Abstract Text: 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). In addition, polymorphisms in MHC class I are associated with ACPA+ RA, including HLA-B*08 allele which harbors aspartic acid at position 9, suggesting that CD8 T cells can contribute to ACPA+ RA pathogenesis. We previously identified clonally expanded cytotoxic granzyme B+ CD8 T cells that target citrullinated antigens, and demonstrated that they are present in blood and synovium in RA; however, the underlying mechanisms by which these autoreactive CD8 T cells are activated to mediate joint tissue destruction in RA are unknown. Here, we demonstrate that oral mucosal breaks of bacteria provide an antigenic source of citrullinated proteins through neutrophil NETosis. We identify that citrullinated proteins are recognized and internalized by antigen-specific 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-CD8 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 may lead to synovitis and joint destruction in ACPA+ RA.