MACROPHAGE MEDIATED IMMUNOREGULATION VIA TRYPTOPHAN

DESCRIPTION: (Adapted from the applicant's abstract) Macrophages phagocytose microorganisms and present antigens to T cells. Paradoxically, however, macrophages are also professional scavengers which normally phagocytose and present antigens derive from self proteins. The long-term goal of this project is to identify the mechanism by which macrophages inhibit autoimmune responses to these self antigens. The applications have identified a novel mechanism whereby macrophages may present antigens in an immunosuppressive, rather than immunostimulatory fashion. They show that macrophages that have differentiated under the influence of macrophage colony-stimulating factor (MCSF) inhibit attempted T cell activation. The mechanism of this inhibition is massive induction of the enzyme indoleamine 2, 3- dioxygenase (IDO), which selectively degrades the essential amino acid tryptophan. Simultaneously, MCSF-derived macrophages markedly increase trypthphan uptake via induction of a novel high-affinity, tryptophan- selective transport pathway. The applicants hypothesize that the combination of these two mechanisms allows macrophages to rapidly deplete tryptophan from the local microenvironment, thus aborting normal T cell activation. Consistent with the proposed role of IDO in suppresssing T cells, the applicants show that pharmacologic inhibition of IDO in vivo results in enhanced activation of autoreactive T cells, and that inhibition of IDO activity in placenta results in rapid, uniform, T cell-mediated rejection of all allogeneic fetuses. The aims of the current proposal are to: (1) test the hypothesis that a synergistic combination of IFNgamma and CD40-ligand expression by T cells triggers IDO expression in macrophages, and characterize the effect of the resulting tryptophan depletion on T cell activation; (2) use a transgenic mouse model to test the hypothesis that IDO-expressing macrophages inhibit autoreactive T cell activation in vivo; and (3) define the functional characteristics and regulation of the high- affinity tryptophan transport system. These studies will define a fundamental and previously unsuspected mechanism of T cell regulation imposed by cells of the innate immune system.