Granzyme K+ CD8 T cells form a core population in inflamed human tissue

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)-gamma 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 T-teK CD8 cells. Armed to produce cytokines in response to both antigen-dependent and antigen-independent stimuli, CD8 T-teK cells have the potential to drive inflammation.

Automated summary

CD8 T cells play a significant role in the pathogenesis of rheumatoid arthritis by producing pro-inflammatory cytokines. These CD8 T cells are abundant in synovial tissue and belong to an effector population characterized by high expression of granzyme K and low expression of granzyme B and perforin. They are clonally expanded in synovial tissues and maintain their characteristics in blood, suggesting their enrichment in tissues. They also exist in other tissues and diseases, indicating their role as tissue-associated T cells.