Granzyme K+ CD8 T cells (TteK) form the core population of inflamed human tissue-associated CD8 T cells. In review, 2021

Abstract

T cell-derived pro-inflammatory cytokines are a major driver of rheumatoid arthritis (RA) pathogenesis. While these cytokines have traditionally been attributed to CD4 T cells, we have found that CD8 T cells are similarly abundant in synovium and make more IFN and nearly as much TNF as their CD4 T cell counterparts. Here, we took an unbiased approach to characterize CD8 T cells in RA synovial tissue and fluid. We present single-cell RNA-seq and flow cytometric data indicating that the vast majority of synovial tissue and fluid CD8 T cells belong to a new effector CD8 T cell population characterized by high expression of granzyme K (GzmK) and low expression of granzyme B (GzmB) and perforin, in contrast to cytotoxic T lymphocytes (CTLs). Functional experiments demonstrate that these GzmK+ GzmB+ CD8 T cells are major cytokine producers with low cytotoxic potential. Interestingly, they appear to be preferentially activated by TCR-independent mechanisms such as cytokines, similar to innate-like T cells. Further, we found that transcriptomically similar GzmK-expressing CD8 T cells were also detected in both healthy and diseased bowel and kidney in an unbiased single-cell integration anlaysis, suggesting that this CD8 T cell population, which we term tissue effector expressing GzmK+ (TteK) CD8 T cells, form the core population of tissue-associated T cells in humans. Armed to produce cytokines in response to antigen-independent stimuli, CD8 TteK cells have the potential to break tolerance and drive inflammation and autoimmunity.