The objective of the proposed research is to define the cellular and molecular mechanisms by which the expression of MHC antigens on macrophages is regulated. A major focus will be on how products of activated T cells induce Ia antigens on macrophages and stimulate increases in the levels of H-2 antigens expressed; the increases in Ia antigens are directly related to antigen presentation capabilities. Using biochemical, immunological, and cellular absorption approaches we hope to identify and characterize the active factors, determining whether Ia and H-2 antigen expression is affected by the same or distinct factors and whether these factors correspond to any previously-identified lymphokines. We will also investigate the nature of the macrophage receptors for the factors, one approach being the preparation of monoclonal antibodies to the receptors. The mechanisms by which binding of the factors to the receptors triggers increases in cell surface antigen expression will be explored with both normal macrophages and macrophage cell lines, utilizing a variety of biochemical, molecular biological, and somatic cell genetics approaches. Finally, we will analyze the basis for the regulation of MHC antigen expression during normal macrophage differentiation, using short term cultures of bone marrow macrophages. These studies should reveal the mechanisms which control levels of MHC antigen on macrophages and, more generally, how cells of the immune system interact to regulate their own immunological reactivity.
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