Granzyme K activates the entire complement cascade

Granzymes are a family of serine proteases mainly expressed by CD8⁺ T cells, natural killer cells, and innate-like lymphocytes¹. Although their primary function is thought to be the induction of cell death in virally infected and tumor cells, accumulating evidence indicates certain granzymes can elicit inflammation by acting on extracellular substrates¹. Recently, we found that the majority of tissue CD8⁺ T cells in rheumatoid arthritis (RA) synovium and in inflamed organs across other diseases express granzyme K (GZMK)², a tryptase-like protease with poorly defined function. Here, we show that GZMK can activate the complement cascade by cleaving C2 and C4. The nascent C4b and C2b fragments form a C3 convertase that cleaves C3, enabling assembly of a C5 convertase that cleaves C5. The resulting convertases generate all the effector molecules of the complement cascade: the anaphylatoxins C3a and C5a, the opsonins C4b and C3b, and the membrane attack complex. In RA synovium, GZMK is enriched in regions with abundant complement activation, and fibroblasts are the major producers of complement proteins that serve as substrates for GZMK-mediated complement activation. Further, Gzmk-deficient mice have less severe arthritis and dermatitis with concomitant decreases in complement activation. Our findings describe the discovery of a previously unidentified mechanism of complement activation that is entirely driven by lymphocyte-derived GZMK. Given the widespread abundance of GZMK-expressing T cells in tissues in chronic inflammatory diseases, GZMK-mediated complement activation is likely to be an important contributor to tissue inflammation in multiple disease contexts.