Cytotoxic CD8 T cells target citrullinated antigens in rheumatoid arthritis.

The immune mechanisms that mediate synovitis and joint destruction in rheumatoid arthritis (RA) remain poorly defined. Although increased levels of CD8 T cells have been described in RA, their function in pathogenesis remains unclear. Here we perform single cell transcriptome and T cell receptor (TCR) sequencing of CD8 T cells derived from anti-citrullinated protein antibodies (ACPA)+ RA blood. We identify GZMBCD8 subpopulations containing large clonal lineage expansions that express cytotoxic and tissue homing transcriptional programs, while a GZMKCD8 memory subpopulation comprises smaller clonal expansions that express effector T cell transcriptional programs. We demonstrate RA citrullinated autoantigens presented by MHC class I activate RA blood-derived GZMBCD8 T cells to expand, express cytotoxic mediators, and mediate killing of target cells. We also demonstrate that these clonally expanded GZMBCD8 cells are present in RA synovium. These findings suggest that cytotoxic CD8 T cells targeting citrullinated antigens contribute to synovitis and joint tissue destruction in ACPA+ RA.