LAUSR

T cell–derived pro-inflammatory cytokines are a major driver of rheumatoid arthritis (RA) pathogenesis. Although these cytokines have traditionally been attributed to CD4 T cells, we have found that CD8 T cells are notably abundant in synovium and make more interferon (IFN)–γ and nearly as much tumor necrosis factor (TNF) as their CD4 T cell counterparts. Furthermore, using unbiased high-dimensional single-cell RNA-seq and flow cytometric data, we found that the vast majority of synovial tissue and synovial fluid CD8 T cells belong to an effector CD8 T cell population characterized by high expression of granzyme K (GzmK) and low expression of granzyme B (GzmB) and perforin. Functional experiments demonstrate that these GzmK+ GzmB+ CD8 T cells are major cytokine producers with low cytotoxic potential. Using T cell receptor repertoire data, we found that CD8 GzmK+ GzmB+ T cells are clonally expanded in synovial tissues and maintain their granzyme expression and overall cell state in blood, suggesting that they are enriched in tissue but also circulate. Using GzmK and GzmB signatures, we found that GzmK-expressing CD8 T cells were also the major CD8 T cell population in the gut, kidney, and coronavirus disease 2019 (COVID-19) bronchoalveolar lavage fluid, suggesting that they form a core population of tissue-associated T cells across diseases and human tissues. We term this population tissue-enriched expressing GzmK or TteK CD8 cells. Armed to produce cytokines in response to both antigen-dependent and antigen-independent stimuli, CD8 TteK cells have the potential to drive inflammation. Description GzmK+ GzmB+ CD8 T cells are enriched in inflamed joints in patients with rheumatoid arthritis and represent a distinct effector T cell type. Influencing inflammation Characterizing the cell types that drive rheumatoid arthritis (RA) may lead to new treatment options for patients with RA and other autoimmune diseases. In this study, Jonsson et al. characterized T cell subsets in synovium samples from patients with RA. Although CD4 T cells were present in synovial samples, CD8 T cells were similarly abundant. These CD8 T cells, which have not historically been considered drivers of RA, were highly activated and expressed granzyme K. Furthermore, granzyme K–expressing CD8 T cells were also enriched in inflamed tissue associated with other autoimmune diseases and COVID-19, suggesting that these cells may be associated with different types of human inflammation.