NIH R01 · 2025
CD8 T cell derived Granzyme K activates complement that drives synovial fibroblast inflammation
The role of T cells in RA is established, but nearly all research has focused on CD4 T cells. We have shown that CD8 T cells are similarly expanded and activated in inflamed RA synovium yet do not belong to the typical granzyme (Gzm) B+ cytotoxic T lymphocyte (CTL) subset. Instead, they express high levels of GzmK whose function is not well defined. Remarkably, we find that GzmK drives a new pathway of complement activation. We show that GzmK can cleave C4 and C2 into C4b and C2a to generate an active C3 convertase (C4b2a) that cleaves C3 to C3a and C3b. We show that fibroblasts express the highest levels of complement components C2, C3 and C4 in the synovium and can secrete these proteins…
From the public funding record at NIH RePORTER. Describes the funded project, not the reviews below.