Clonally Expanded Cytotoxic CD8 +T cells Target Citrullinated Antigens In ACPA+ Rheumatoid Arthritis

Abstract

Abstract 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 role 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 of 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 have a role in contributing to synovitis and joint tissue destruction in ACPA+ RA. The study was supported by following grants: National Institutes of Health grant R01 AR063676, U19 AI110491, R01 AR078268, and Janssen Biotech, Inc.