Tu125 - Granzyme K Activates a New Complement Pathway

Michael Brenner, MD – Harvard Medical School / Brigham and Women's Hospital; Helena Jonsson, MD PhD – Harvard Medical School / Brigham and Women's Hospital; Erin Theisen, MD PhD – Harvard Medical School / Brigham and Women's Hospital

Abstract Text: The role of T cells as major drivers of rheumatoid arthritis (RA) pathogenesis is well established, but nearly all research has focused on CD4+ T cells. We have recently identified a new effector CD8+ T cell population that is abundant in inflamed RA synovium. Unlike cytotoxic T lymphocytes, these CD8+ T cells have low cytotoxic potential, expressing low levels of granzyme B and perforin. Instead, these CD8+ T cells express high levels of granzyme K (GzmK), a granzyme that does not drive apoptosis of target cells. Similar GzmK+ CD8+ T cells are also highly enriched in many other inflamed tissues, although their function remains unclear. Here, we report that GzmK activates a new complement pathway by cleaving C4 and C2 to generate C3 convertases (C4b + C2a) that cleave C3 and evolve into C5 convertases (C4b + C2a + C3b). In doing so, GzmK elicits activation of the entire complement cascade, generating the anaphylatoxins C3a and C5a, the opsonin C3b, and the membrane attack complex. Further, we demonstrate that synovial fibroblasts are the dominant source of complement in the synovium, and GzmK cleaves fibroblast-derived C4 and C2 to activate the complement cascade. Our findings illustrate the existence of a fourth pathway of complement activation, where GzmK secreted by CD8+ T cells cleaves complement components derived from fibroblasts and other cells. This novel pathway is likely to be important at sites of inflammation where GzmK-expressing CD8+ T cells are enriched, where it may contribute to the perpetuation of local tissue inflammation.