Role of natural killer cytotoxic factors in the mechanism of target-cell killing by natural killer cells.

Studies on the mechanism of cell-mediated cytotoxicity (CMC) have suggested a stimulus-secretion model and implicated a role of soluble cytotoxic mediators. Our studies in the natural killer (NK) system provide several lines of evidence for the involvement of natural killer cytotoxic factors (NKCF) in NK CMC and led to the development of a model for the NK lytic mechanism. This model delineates several interactions between NK cells and targets that are deemed necessary to achieve target-cell lysis. The first stage is the interaction of the effector with the target cell, resulting in contact and adhesion. This is presumably mediated by NK recognition structures and target-cell structures. Following binding, the target cell stimulates the NK cell to release NKCF. This step is functionally distinct from the initial effector-target binding. The trigger mechanism for release of NKCF appears to be dependent on protein kinase C. The released NKCF binds to NKCF binding sites on the target cell followed by "processing" or "internalization" and, ultimately, resulting in cell death. This model has been shown to be useful in investigating the mechanism of defective NK activity in certain disease states. Biochemical analysis and comparative studies suggest that NKCF is a distinct molecule from other cytotoxins studied to date. The studies in the NK CMC system supporting a role of cytotoxic mediators also suggest a possible role for cytotoxic factors in other cytotoxic systems. Furthermore, the selective susceptibility to lysis of tumor or infected cells by NKCF suggests a possible role of their effectiveness in in vivo therapy.