Autoimmune rheumatologic diseases
CD8 T cells are enriched in synovium and synovial fluid of patients with rheumatoid arthritis (RA), yet little is known about their role in autoimmune arthritis. As suggested by recent single-cell RNA-sequencing data from the Accelerating Medicines Partnership, we have found that the majority of CD8 T cells in synovial tissue and fluid express granzyme K (GzmK), a marked enrichment compared to blood. GzmK is a protease which, unlike granzyme B (GzmB), does not activate apoptotic caspases. In contrast, very few synovial CD8 T cells express GzmB alone, the pattern seen in cytotoxic T lymphocytes (CTLs). Relative to GzmK-negative CD8 T cells, GzmK+ CD8 T cells in blood express higher frequencies of chemokine receptors CCR2 and CCR5, which direct cells towards sites of inflammation, suggesting that GzmK+ CD8 T cells are preferentially recruited to inflamed joints in RA. We have found that CD8 T cells play several roles in RA synovium. First, synovial CD8 T cells express IFNγ at a higher frequency and TNF at a similar frequency as CD4 T cells after stimulation. Second, GzmK itself has pro-inflammatory effects on synovial fibroblasts, inducing them to produce IL-6, CCL2, and reactive oxygen species, all of which are upregulated in inflamed synovium. Together, these findings form the basis of a new model of CD8 T cell migration and function in RA and potentially other immune responses. We have also developed methods for isolation of RNA from fixed and intracellularly stained cells to further study GzmK+ CD8 T cells by low-input RNA-seq.