The ability of macrophages to destroy foreign cells such as bacteria and neoplastic cells forms the basis of an important mechanism of host defense. Although macrophage cytocidal activity appears to be a composite of three reactions involving activation, recognition, and target cell killing, detailed information of the mechanisms involved in these processes has remained scarce. This research seeks to elucidate the molecular events that lead to macrophage activation and to determine the effect of activation on macrophage recognition reactions and effector cell function. In the past, we placed particular emphasis on the purification and characterization of the soluble T-lymphocyte product, denoted macrophage activating factor (MAF), which is responsible for inducing macrophage cytocidal activity. On the basis of a variety of biosynthetic, physiochemical, and immunochemical criteria, we have found that the MAF activity produced by a murine T-cell hybridoma is totally attributable to gamma interferon (IFN-gamma). During the past year, we characterized a specific cell surface receptor for IFN-gamma that regulates macrophage activation. We also produced monoclonal antibodies to human and murine IFN-gamma and used these reagents to demonstrate the presence of distinct functional domains on IFN-gamma that induce different cellular activities. These antibodies have also been used to show that IFN-gamma is the major MAF made by normal T lymphocytes. Because of the recent reports that certain complement proteins can mimic specific lymphokines and influence activation of mononuclear phagocytes, the role of complement in the induction of macrophage cytocidal activity also will be examined. The membrane structures on macrophages that recognize target cells will be characterized. Phagocyte complement receptors also will be defined. A detailed analysis will be performed to quantitate the effects of activation on the function of these two types of cellular recognition structures. The results of these studies should provide additional insights into the molecular basis of macrophage function and thus enhance our understanding of the host defense system. (HF)
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