Unlocking the secrets of cytotoxic granule proteins

Cytotoxic lymphocytes largely comprise CD8(+) cytotoxic T cells and natural killer cells and form the major defense of higher organisms against virus- infected and transformed cells, A key function of cytotoxic lymphocytes is to detect and eliminate potentially harmful cells by inducing them to under go apoptosis, This is achieved through two principal pathways, both of whic h require direct but transient contact between the killer cell and its targ et. The first, involving ligation of TNF receptor-like molecules such as Fa s/CD95 by their cognate ligands, results in mobilization of conventional, p rogrammed cell-death pathways centered on activation of pro-apoptotic caspa ses, This review concentrates on the second pathway, in which the toxic con tents of secretory vesicles of the cytotoxic lymphocyte are secreted toward the target cell, and some toxins penetrate into the target cell cytoplasm and nucleus. In addition to invoking a powerful stimulus to caspase activat ion, this "granule-exocytosis mechanism" provides a variety of additional s trategies for overcoming inhibitors of the caspase cascade that may be elab orated by viruses. The key molecular players in this process are the pore-f orming protein perforin and a family of granule-bound serine proteases or g ranzymes, The molecular functions of perforin and granzymes are under inten se investigation in many laboratories including our own, and recent advance s will be discussed. In addition, this review discusses the evidence pointi ng to the importance of perforin and granzyme function in pathophysiologica l situations as diverse as infection with intracellular pathogens, graft ve rsus host disease, susceptibility to transplantable and spontaneous maligna ncies, lymphoid homeostasis, and the tendency to auto-immune diseases.