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- Title
Cytotoxic CD8<sup>+</sup> T cells target citrullinated antigens in rheumatoid arthritis.
- Authors
Moon, Jae-Seung; Younis, Shady; Ramadoss, Nitya S.; Iyer, Radhika; Sheth, Khushboo; Sharpe, Orr; Rao, Navin L.; Becart, Stephane; Carman, Julie A.; James, Eddie A.; Buckner, Jane H.; Deane, Kevin D.; Holers, V. Michael; Goodman, Susan M.; Donlin, Laura T.; Davis, Mark M.; Robinson, William H.
- 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. 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.
- Subjects
RHEUMATOID arthritis; T cell receptors; T cells; ANTIGENS; BLOOD cells; CYTOTOXIC T cells; AUTOANTIGENS
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-022-35264-8