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 GZMB⁺CD8⁺ subpopulations containing large clonal lineage expansions that express cytotoxic and tissue homing transcriptional programs, while a GZMK⁺CD8⁺ 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 GZMB⁺CD8⁺ T cells to expand, express cytotoxic mediators, and mediate killing of target cells. We also demonstrate that these clonally expanded GZMB⁺CD8⁺ 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.