Natural killer (NK) cells are a discrete subset of lymphocytes that can be distinguished from T cells and B cells by the expression of characteristic surface antigens and by distinct functional attributes. Through identification and subsequent characterization of the cellular functions of specific receptors expressed by human NK cells, previous studies have led to a better understanding of the role these cells play in the immune response and have helped to develop new approaches to modulate NK cell function in patients with cancer. As with all other lymphocytes, cytokines play a central role in regulating the differentiation, growth, secretary functions and cytolytic activity of NK cells. Although many cytokines influence NK cells, IL-2 and IL-12 appear to be among the most potent stimulators of NK cells. Nevertheless, the mechanisms whereby these agents regulate specific cellular functions remain poorly defined. It is known that IL-2 and IL-12 regulate the function of immune cells through their interaction with specific cell surface receptors, but the cell surface expression of these receptors is itself regulated and varies in different cell types. Co-stimulatory molecules that do not directly interact with either the cytokine or the specific receptor also influence the cell's ability to respond to these cytokines. Moreover, the intracellular signaling pathways activated through specific receptors also appear to be sites for regulating the functional response to these cytokines. In contrast to the IL-2 receptor (IL-2R) that has been well characterized and know to consist of at least 3 subunits, the receptor for IL-12 and its various subunits has not been completely defined. To develop a better understanding of the mechanisms whereby IL-2 and IL-12 regulate similar or different NK cell functions, a series of experiments will be carried out in 3 Specific Aims: 1) Characterization of IL-12 receptor structure and function in human NK cells; 2) Characterization of regulatory elements and co-stimulatory signals required for IL-2 and IL-12 receptor function; and 3) Functional characterization of signaling pathways for NK cell activation. Results in NK cells will be compared to T cells where functional responses are known to be different. In addition, these studies will be extended to examine cells obtained from patients receiving either IL-2 or IL- 12 to develop a better understanding of the immunologic effects of this treatment. Developing a better understanding of the cellular effects and interactions of these 2 cytokines in NK cells, will not only improve our understanding of how specific cellular functions are regulated, but may also lead to improved immune therapies in patients with cancer or immune deficiency.
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