The purpose of this proposal is to study the regulation of macrophage function, primarily as it affects T cell growth. We will evaluate both in vivo and in vitro, the control of two of the predominant immunoregulatory functions of the macrophage, antigen presentation and cytocidal capacity. In Project 1, we will determine the temporal relation of (a) Ia expression and antigen presentation function with (b) cytocidal activity directed against tumor cells (the traditional target of macrophage lytic function) as well as T cell lines and clones. We have evidence that the past history of both T cells and macrophages may predispose them towards an interaction leading ultimately to either T cell growth or death. We will focus on defining the mode of action of interferon (IFN)-gamma, a mediator known to induce both Ia and antigen-presentation capacity as well as tumoricidal function, in the context of several important endogenous and environmental factors, e.g., adherence, serum factors, and bacterial products, that dramatically module its effects. Our approach will consist of quantitating Ia expression, the growth of T cell clones, and tumor cell lysis. Moreover, we will also study macrophages fixed in paraformaldehyde after antigen processing, in order to assess the relevance of transient changes in macrophage Ia expression, as well as to evaluate the function of different macrophage populations in the absence of any secretory or cytocidal function. In Project II, we develop this theme further by focusing on the nature of the interaction of IFN-gamma with its receptor. We will define IFN binding parameters in macrophages at different states of activation, as well as receptor distribution in an effort to determine if quantitative or qualitative changes in IFN binding may determine whether it induces antigen presentation or cytocidal activity. Subsequently, we will evaluate the affects of those endogenous and environmental factors (as described in Project I) that most dramatically regulate function, for their capacity to modulate IFN interaction with its receptor. Ia expression and cytocidal activity may be two critical facets of the antigen-presentation function of macrophages. We are proposing an integrated study of the conditions that may regulate the temporal relation and magnitude of these events as a basis for understanding how the ultimate function expressed by this multifaceted cell is regulated.
