Regulation of T cell immunity by indol 2,3 dioxygenase

DESCRIPTION (provided by the applicant): The long-term objectives to which the proposed studies relate are to identify and evaluate natural processes that regulate immune responsiveness towards tissue allografts, tumors and cells infected with pathogenic organisms. The specific goal of the studies proposed is to evaluate the role of cells expressing indoleamine 2,3 dioxygenase (IDO), which catabolizes tryptophan, in suppressing T cell mediated immunity directed against allogeneic tissues and tumor cells. The hypothesis to which these studies relate is that cells expressing IDO suppress or modify T cell responsiveness providing increased protection against T cell mediated immunity for cells in local tissue microenvironments. We will also conduct experiments to evaluate mechanistic links between T cell and complement activation that are suppressed by IDO activity in local tissue microenvironments. To evaluate the role of IDO in inflammation and immunosuppression we will utilize two new strains of genetically-manipulated mice generated recently in our laboratory. We will measure inflammatory and T cell responses in mice that do not express IDO (IDO-deficient mice) and in transgenic mice that over-express IDO in response to inflammatory signals (MHCII-IDO mice). In Aim 1 we will test the hypothesis that targeted deletion of IDO leads to enhanced accessory and antigen-presenting cell functions for T cell and complement activation and targeted IDO over-expression suppresses T cell and complement activation. In Aim 2 we will evaluate pregnancy outcomes for allogeneic and syngeneic fetuses in matings between parents that carry defective IDO alleles. In Aim 3 we will evaluate immune responses to tissue allografts from IDO-deficient and MHCII-IDO recipient and donor mice. In Aim 4 we will test the hypothesis that IDO activity suppresses host anti-tumor immunity. Data obtained from these studies will reveal the extent to which IDO activity in local tissue microenvironments influences T cell activation and elucidate the mechanism by which T cell driven complement deposition occurs in pregnant and tumor-bearing mice when IDO activity is blocked. Knowledge gained from the proposed studies will allow us to evaluate the potential for adapting the IDO immunosuppressive mechanism to facilitate tissue allograft acceptance and develop novel therapeutic strategies to help eradicate tumors in immunocompetent hosts.