Journal Article

Cytotoxic CD8+ T cells target citrullinated antigens in rheumatoid arthritis

Holers, V. Michael, Rao, Navin L., Buckner, Jane H., Younis, Shady, Moon, Jae-Seung, Ramadoss, Nitya S., Robinson, William H., Iyer, Radhika, Donlin, Laura T., Becart, Stephane, Deane, Kevin D., Goodman, Susan M., Carman, Julie A., Sheth, Khushboo, James, Eddie A., Sharpe, Orr, Davis, Mark M.

2023

Overview

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. The immune mechanisms underlying synovitis and joint tissue destruction in rheumatoid arthritis (RA) remain incompletely defined. Here, the authors demonstrate that ACPA+ RA patients have activated clonally expanded cytotoxic GZMB + CD8+ T cells in blood and synovium that target and are activated by citrullinated antigens to mediate cell killing.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/31 / 38 / 38/39 / 38/90 / 38/91 / 631/250/1619/554/1834/1269 / 631/250/2152/1566/1618 / 631/250/2502 / 631/250/38 / 692/4023/1670/498 / Antibodies / Antigens / Arthritis / Arthritis, Rheumatoid / Autoantibodies / Autoantigens / Blood / CD8 antigen / CD8-Positive T-Lymphocytes - metabolism / Citrulline / Cytotoxicity / Destruction / Humanities and Social Sciences / Humans / Joints (anatomy) / Lymphocytes / Lymphocytes T / Major histocompatibility complex / Memory cells / multidisciplinary / Pathogenesis / Receptors, Antigen, T-Cell / Rheumatoid arthritis / Science / Science (multidisciplinary) / Subpopulations / Synovial Membrane - metabolism / Synovitis / Synovium / T cell receptors / Transcriptomes