Cytotoxic CD8+ T cells target citrullinated antigens in rheumatoid arthritis
- PMID: 36658110
- PMCID: PMC9852471
- DOI: 10.1038/s41467-022-35264-8
Cytotoxic CD8+ T cells target citrullinated antigens in rheumatoid arthritis
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 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.
© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
Conflict of interest statement
The authors declare no competing interests.
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Comment in
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Citrulline immunity in RA: CD8+ T cells enter the scene.Nat Rev Rheumatol. 2023 May;19(5):259-260. doi: 10.1038/s41584-023-00945-1. Nat Rev Rheumatol. 2023. PMID: 36914789 No abstract available.
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