Multiple Lytic Pathways in Cytotoxic T Lymphocytes

The study of the mechanism of cell-mediated cytotoxicity received renewed interest with the introduction of a rather elegant and simple model: exocytosis of toxin-containing granules from cytotoxic effector cells upon encounter with and activation by their specific target cells (Dennert and Podack, 1983; Henkart et al., 1984; Podack and Konigsberg, 1984; Young and Cohn, 1986). A pore-forming protein, perforin (also called cytolysin), was identified first in the cytoplasmic granules of natural killer (NK) cells, and subsequently in cytotoxic T lymphocytes (CTL). Binding of CTL and NK cells to their target cells is proposed to trigger a degranulation event, releasing perforin monomers which assemble in the presence of Ca2+ into complement-like pore structures that insert into the target membrane, thereby causing damage to the target cell. Initially it seemed that this model could adequately account for the known features of antigen-specific, CTL-mediated cytotoxicity. That perforin exists is beyond question, the gene having been cloned and sequenced by several laboratories. A role for perforin in cell-mediated cytolysis has been greatly strengthened by recent antisense (AchaOrbea et al., 1990) and gene transfection (Shiver and Henkart, 1991) experiments.