Granzyme K Drives a New Pathway of Complement Activation That Contributes to Disease Pathology

Carlos Donado – Brigham and Women's Hospital; Madison Fairfield – Brigham and Women's Hospital; A. Helena Jonsson – University of Colorado Anschutz Medical Campus; Michael Brenner – Brigham and Women's Hospital

Abstract Text: Granzyme K (GZMK) expressing CD8+ T-cells have recently been defined as the predominant CD8+ T-cell population in inflamed tissues in multiple autoimmune diseases. However, the overall function of GZMK has been relatively undefined. Here, we show that GZMK is a novel activator of the complement cascade. GZMK cleaves C2 to C2b and C4 to C4b to form an active C3 convertase that cleaves C3 into bioactive C3a and C3b. GZMK further forms active C5 convertases that generate C5a and the membrane attack complex, thus generating all key components of the complement cascade. GZMK is continuously released from CD8+ T-cells in an antigen-independent manner. Upon release, GZMK binds to negatively charged surface molecules through electrostatic interactions, and membrane bound GZMK is more efficient at forming C3 convertases. In human rheumatoid arthritis synovium, we find evidence of increased complement activation near GZMK+ cells. Importantly, in a model of inflammatory arthritis, Gzmk-/- mice have less severe joint swelling than Gzmk+/+ or Gzmk+/- mice. In a second disease model, imiquimod-induced dermatitis as a model of psoriasis, Gzmk-/- mice have less severe erythema, scaling and thickening of skin compared to Gzmk+/+ or Gzmk+/- mice. Strikingly, Gzmk-/- mice have markedly less C3d and C4d, products of complement pathway activation. These data suggest GZMK is driving the activation of the complement cascade in vivo. Taken together, we define a new pathway of complement activation that is dependent on GZMK and has the potential to drive inflammation in a variety of tissues and disease states.