The purpose of the proposed research is to determine how plasma lipoproteins and apolipoproteins bound to lymphocyte membrane receptors - termed proliferation-restraint receptors - inhibit mitogenic recruitment of the cells into and passage through the cell cycle, thereby inhibiting mitogen-induced cell proliferation. The suppressor molecules inhibit biochemical process -e.g., enhanced metabolism of phosphatidylinositol (PI) - which occur within the first hours post-stimulation. Inhibition correlates directly with extent of receptor occupancy. The hypothesis to be tested is that PI metabolism is important in the production of growth factors and/or growth factor receptors which are required for the activated cells to undergo mitosis. The hypothesis will be tested in systems containing defined cellular phenotypes and relying on assays in which events can be assessed in idividual cells by flow cytometry. The three specific aims are: (1) to determine the phenotype of the lymphoid cells required to generate the PI response and to modulate suppression of this response by AP/LP, (2) to determine the influence of AP/LP on IL-2 receptor expression and IL-2 production, paying particular attention to the relationship between the PI response, IL-2 receptor expression and IL-2 production, and (3) To characterize the proliferation-restraint receptor by its specificity for well-characterized ligands and its sensitivity to modification-inactivation. The long term goals of the research are (1) to determine the structure of the lymphocyte proliferation-restraint receptor which recognizes apolipoproteins; (2) to elucidate the mechanism by which it functions to restrict lymphocyte proliferation at the molecular level; (3) to identify the cells, lymphocyte and nonlymphocyte, which express it and are therefore sensitive to its function; and (4) to understand the factors which regulate its expression and its activity. Lipoproteins are natural modulators of the functional capacity of the immune system. Suppression of immune responsiveness by lipoproteins is important in diseases such as cancer in which host immune competence may be a primary defense mechanism. In cell biology/physiology, the proliferation-restraint receptor offers the opportunity to define recruitment of lymphocytes from the nonproliferating state in molecular terms.
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