Natural killer (NK) cells, cytotoxic T-lymphocytes (CTL's), and mononuclear phagocytes (MP) represent three major systems of host defense against tumors. Our laboratory is actively involved in the molecular dissection of cell-surface events important in the cytotoxic response mediated by these cells, through the use of monoclonal antibodies as probes of structure and function. In this project, we propose to continue our studies examining the role of the Lymphocyte Function-Associated Antigen-One (LFA-1) heterodimeric family of surface glycoproteins on cytotoxic cells, with special emphasis on the NK system and a closely-related effector cell, Lymphokine (IL-2)-Activated Killer Cells. Our laboratory is currently exploring the following hypotheses in cytotoxic systems: (1) that cell surface density of LFA-1 family members is important in expression of cell-mediated cytotoxicity in these systems; (2) that LFA-1 subserves non-adherence related function(s) in the NK system, possibly playing a role in a late step in the cytolytic mechanism or in more global regulation of cellular processes (e.g., transmembrane signalling events); and (3) that one important effect of IL-2 in modulating cytolytic activity is in enhancing expression of LFA-1, through as yet unknown mechanisms. In this Competing Continuation Application, we propose a series of experiments designed to further test these hypotheses through detailed study of the structure, function, expression, and biosynthesis of this important family of surface molecules, as well as proposals to attempt to isolate and identify the putative target cell ligand for LFA-1 in the NK system. In so doing, we will continue to pursue our long-term goal of better understanding, at the molecular level, cell-mediated host defense against tumors.
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