The ability of certain cells in the immune system, including cytotoxic T lymphocytes (CTL) and natural killer (NK) cells, to mediate the cytotoxicity of allogeneic, virally-infected or malignant target cells is well established. Several investigations strongly support the in vivo importance of these cellular cytotoxicity reactions in defense against certain infections, in immunosurveillance, and in the regulation of other cells within the immune system. Laboratory investigations aimed at a better understanding of the mechanism(s) involved in these reactions have been severely hampered by the heterogeneity of cytotoxic cell populations and the lack of precise methods for quantitating cellular cytotoxicity reactions and the individual stages in the overall cytolytic process. Recent advances, including (a) development of procedures for the isolation and propagation of cloned lines of rodent and human cytotoxic cells, (b) production of a few hybridomas from cytotoxic cells, (c) development of kinetic models and precise methods for quantitating cellular cytotoxicity reactions and the rate constants for each of the steps involved in this process, and (d) detection of certain proteins that appear to be involved in the cytolytic process, now allow for clarification of the cytotoxicity mechanism employed by these cells. Experiments will refine and extend the application of a multistep kinetic model for cellular cytotoxicity reactions by testing its applicability to cytolysis reactions mediated by cloned cytotoxic cells and cytolytic factors. These studies will include the precise measurement of the rate of interaction of these cells and factors with various target cells, rates of lytic programming, and rates of killer cell-independent lysis, as well as the effects of experimental conditions on the rates of these processes. These experiments will provide valuable information about the relationship(s) between these cytotoxic cells, the mechanism(s) involved in these reactions, and their regulation. A clearer understanding of these phenomena is needed to clarify the physiologic role of these cells, to facilitate attempts to enhance the natural immunity of cancer patients, and to develop more quantitative and standardizable assays for cytotoxic activity of normal and diseased individuals.
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