Proteases and cell-mediated cytotoxicity

Cytotoxic T lymphocytes and natural killer cells represent the body's primary defense against viral-infected and tumorigenic cells. The classically described mechanism by which these cells induce target cell death is granule mediated: cytolytic granules within the killer cell are directionally exocytozed toward the target cell, and the granule contents inflict a "lethal hit" on the target cell. A second mechanism of cytotoxicity is now known to exist, and utilizes cell surface receptors on the target cell, for which the ligand is expressed on the killer cell. Receptor oligomerization results in the recruitment of cytoplasmic proteins to the receptors and the transduction of a death signal to the target cell. In both granule-and receptor-mediated cytotoxicity, the target cell dies through a defined series of steps, which together are termed apoptosis. Recent work on apoptosis has defined a family of cysteine proteases, the caspases, which appear to be involved in the initiation of apoptosis in response to a number of stimuli. This review focuses on studies that link these proteases to target cell death induced by cytotoxic cells.