IL-15 drives antigen-independent increase in granzyme K+B+ CD8 T cells enriched in rheumatoid arthritis joints

Objectives CD8 T cells co-expressing granzymes K and B (GzmK + B+) are enriched in the joint compared with peripheral blood and have been implicated in the pathogenesis of rheumatoid arthritis (RA). However, it remains unclear whether the enrichment of GzmK+B+ subsets is specific to RA. In addition, the mechanism underlying the generation of GzmK + B + CD8 T cells remains unknown.Methods Characteristics of CD8 T cells in the synovium of patients with RA and osteoarthritis (OA) were examined by a flow cytometer. Public database of single cell RNA sequence (scRNA-seq) of RA and OA synovium was analyzed, and the results were verified by in vitro culture experiments. Flow cytometric analysis of viral antigen-specific CD8 T cells identified by MHC class I tetramer was performed.Results GzmK+B+ subset in CD8 T cells was more enriched in RA than OA joint, whereas no difference was observed in the frequency of GzmK + B- subset. In silico analysis of public database recapitulated these results and suggested the transition from GzmK + B- to GzmK+B+ subset which is mediated by IL-15- but not TCR-signaling. IL-15 induced an increase in GzmK + B + CD8 T cells from RA and OA joints in vitro. Viral antigen specific bystander CD8 T cells in RA joints are also enriched of GzmK+B+ subset.Conclusions Our results suggest that increased IL-15 in RA joints promotes bystander activation of CD8 T cells, leading to the enrichment of GzmK + B + CD8 T cells, which are implicated in the pathogenesis of RA.