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.

Type 17 specific immune pathways are active in early spondyloarthritis

“…Furthermore, a recent study reported the presence of clonally expanded cytotoxic CD8 + T cells in the blood and synovium of ACPA + RA patients. These cytotoxic CD8 + T cells were activated by citrullinated antigens in an HLA class I-dependent manner leading to expression of pro-in ammatory and cytolytic mediators (IFNg and/or GzmB) (39).…”

Emerging synovial cell states in rheumatoid arthritis as potential therapeutic targets

“…Relative to ACPA-patients, T PH cells were enriched in the synovial fluid of ACPA þ RA patients, with an upregulation in the expression of GPR56 and LAG-3. Further studies are needed, but therapies that modulate targets like GPR56 hold considerable potential, considering the distinct and robust expansion of T PH cells in the RA synovium [30 ]. The recent discovery of two CD8 þ T-cell subsets has particularly improved our understanding of the role of these cells in the pathogenesis of RA.…”

“…In addition, a cytotoxic, clonally expanded GZMB + CD8 + subpopulation was demonstrated to be activated by citrullinated peptide antigens in CCP+ RA synovium (Table 1). These cells may represent a new autoreactive T-cell subset that directly contribute to joint destruction and further provide strong rationale for additional development of therapeutics targeting cytotoxic CD8+ T cells [33 ▪ ].…”

Proinflammatory impact of putative viral-specific CD8+ T cells infiltrating new-onset seropositive rheumatoid arthritis synovium

“…Single-cell RNA-sequencing (scRNA-seq) of RA PB and ST identified CD8 + cytotoxic T lymphocytes (CTL) expressing granzyme B and/or K 10 that were highly activated, and produce IFN-γ and TNF in response to citrullinated self-antigens in the synovium of predominantly longstanding RA patients 11,12 . Intriguingly, inguinal lymph node biopsies from asymptomatic ACPA + or rheumatoid factor (RF) + at-risk individuals as well as patients with recent-onset RA, were enriched in CD8 + memory, CD69 + and CXCR5 + TFH relative to healthy-control biopsies 13,14 , implicating CD8 + TEM in the earliest stages of the RA immune response.…”

“…Clonally-expanded T cells have been demonstrated in ST and PB of RA patients 12,25,26,27 , and in recent-onset RA patients, highly expanded TCR clonotypes were identified in multiple joints 25,26 . However, the degree of clonal dominance (exclusive expansion of a few clones) decreased with longer disease duration 25 suggesting that repertoire studies in early disease may yield the greatest insight to disease-relevant antigens and the role of T cells in early disease.…”