The role of granzyme B cluster proteases in cell-mediated cytotoxicity

Granzymes are neutral serine proteases that are stored in the specialized lytic granules of cytotoxic lymphocytes. A mutation introduced into the granzyme B locus leads to a severe defect in the ability of cytotoxic lymphocytes to induce apoptosis in, susceptible target cells, and reduces the severity of class I-dependent acute graft-versus-host disease (GVHD). However, granzyme B-independent cytotoxicity also exists: in CD8⁺ cells, most of it is perforin-dependent, but in CD4⁺ cells, the Fas system and an additional pathway are involved. The identification of these pathways and their physiological relevance may lead to new approaches for inhibiting cytotoxic lymphocyte functions.