The long rang objective of this project is to investigate the origin, differentiation, and function of NK cells. The working hypothesis, derived from their research and that of others, is that NK cells represent a relatively homogenous discrete cell type, with various defensive and regulatory activities, including but not limited to cell-mediated cytotoxicity and that the effectiveness and specificity of NK cells in vivo depend on a complex network of interactions with humoral factors and other cellular types. Although much progress has been made recently on the characterization of NK cells, their inhibitory and stimulatory receptors, and their ability to produce cytokines, the exact physiological roles of NK cells at the interface of innate and adaptive immunity, and the mechanisms of their activation in response to pathological insults still await a better understanding. Dr. Trinchieri hypothesized that NK cells, in addition to their direct role in innate resistance, play an role in shaping the type of adaptive immune responses and that the cytokines important in regulatory NK cell activity, particularly IFN-alpha and IL-12, and the cell types producing them constitute an important backbone in the immunoregulatory cross-talk between the innate resistance and acquired immunity. In order to understand further this immuno-regulatory mechanism, he proposes to investigate: 1) Proliferation, cytokine production and differentiation of NK cells. 2) Characterization and function of C1.7 Ag, a signal transducing receptor on NK cells and a marker of activation of CD8 t cells. 3) The relationship between IFN-alpha producing cells and dendritic cells and the physiological relevance of IFN-alpha in the interaction of dendritic cells with NK cells and T cells.
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