ACTIVATION OF NON-MHC-RESTRICTED CYTOTOXIC LYMPHOCYTES

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Natural Killer (NK) cells represent the major lymphocyte subset whose functions are elicited, in the initial phases of the host response to a variety of pathogens, and that are capable of cytotoxicity in an MHC- non-restricted fashion. Through production of cytokines, NK cells exert a regulatory role on other cell types and, on the other hand, their own biological functions are regulated by cytokines produced by other mononuclear cell subsets and, possibly, by themselves. Among the known cytokines, only IL-2 and IL-12 have been demonstrated capable of modulating proliferation of these cells directly. We have identified and characterized the biological functions exerted by IL-12 on NK cells and T lymphocytes. IL-12 is a novel cytokine that acts independently from IL-2 to induce activation and proliferation of prestimulated NK and T cells. It enhances spontaneous cytotoxicity of NK cells, induces cytokine production by PBL acting in synergy with IL-2 and a series of other stimuli, variably modulates proliferation of lymphocytes, and affects Th1 cells differentiation. Our data support the contention that the mechanisms by which the two cytokines affect NK and T cell functions are distinct, and likely do depend on induction of different intracellular activation pathways, although in both cases activation of tyrosine kinases may play a major functional role. Understanding the immunobiology of NK cells depends on defining the type of interactions that are elicited to induce production of cytokines and the binding of these to their specific receptors at the surface of the effector cells. In order to start dissecting these conditions we propose: 1) to identify the cell types that are involved in the production of IL-12, with particular attention to mononuclear cell subsets present in minor proportion among lymphocytes (e.g. B lymphocytes and their subsets, basophils, and monocytes), using a combination of cell separation, biochemical and molecular biology techniques; 2) to biochemically and functionally characterize the receptor(s) for this cytokine, focusing on understanding the basis for the receptor-mediated signal-transduction and induced tyrosine kinase activity; and 3) to determine whether IL-12 also acts as a differentiation factor for more immature NK cell populations, utilizing the culture system in which we have demonstrated preferential proliferation of mature NK cells. From the proposed studies we expect to derive relevant information to the immunobiology of NK cells, and of cytokines that enhance the functions of this and other cytotoxic cell types and are, at present considered for possible immunotherapeutic use in several pathological situations.