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.