Cytotoxic CD8+ T cells target citrullinated antigens in rheumatoid arthritis

Jae-Seung Moon, Shady Younis, Nitya S. Ramadoss, Radhika Iyer, Khushboo Sheth, Orr Sharpe, Navin L. Rao, Stephane Becart, Julie A. Carman, Eddie A. James, Jane H. Buckner, Kevin D. Deane, V. Michael Holers, Susan M. Goodman, Laura T. Donlin, Mark M. Davis and William H. Robinson ()
Additional contact information
Jae-Seung Moon: Stanford University School of Medicine
Shady Younis: Stanford University School of Medicine
Nitya S. Ramadoss: Stanford University School of Medicine
Radhika Iyer: Stanford University School of Medicine
Khushboo Sheth: Stanford University School of Medicine
Orr Sharpe: Stanford University School of Medicine
Navin L. Rao: Janssen Research and Development LLC
Stephane Becart: Janssen Research and Development LLC
Julie A. Carman: Janssen Research and Development LLC
Eddie A. James: Center for Translational Immunology, Benaroya Research Institute
Jane H. Buckner: Center for Translational Immunology, Benaroya Research Institute
Kevin D. Deane: University of Colorado Anschutz Medical Campus
V. Michael Holers: University of Colorado Anschutz Medical Campus
Susan M. Goodman: Hospital for Special Surgery
Laura T. Donlin: Hospital for Special Surgery
Mark M. Davis: Stanford University
William H. Robinson: Stanford University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-15

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 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.

Date: 2023
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DOI: 10.1038/s41467-022-35264-8

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