Defining the cellular and molecular mechanism of IDO2 function driving autoimmune vs.protective immune responses - Project Summary Autoimmune diseases are chronic inflammatory diseases that affect more than 50 million Americans, leading to pain, disability, and increased mortality. While drugs to treat autoimmune diseases exist, alleviation of inflammatory symptoms is often associated with severe side-effects, including increased susceptibility to infections and cancer. Our proposal addresses the urgent need to identify new therapeutic targets to address the underlying causes and associated symptoms of these debilitating diseases. In this proposal, we will investigate indoleamine-2,3-dioxygenase (IDO2) as a novel immunomodulatory target for autoimmune diseases. IDO2 is one of two closely related tryptophan catabolizing enzymes expressed primarily in immune cells. Using a combination of genetic and pharmacological studies in the KRN model of inflammatory arthritis, we identified IDO2 as an essential mediator of autoantibody-mediated inflammatory responses and discovered a novel non-enzymatic function of IDO2 that drives autoimmune responses leading to disease. Mechanistic studies implicate the transcription factor Runx1 as a potential component of this previously unknown IDO2 signaling pathway. IDO2 appears to be essential for only some B cell functions, as IDO2 deficient mice develop normal immune cell compartments and mount productive immune responses to challenge with some, but not all, model antigens in vitro and in vivo. A better understanding of IDO2 biology, in particular the roles that enzymatic and non-enzymatic activity have in regulating immune function is necessary to develop IDO2 as a potential therapeutic target for autoimmune disease. Our working hypothesis is that IDO2 modulation of immune responses involves both enzymatic and non-enzymatic pathways with autoreactive B cell activation/autoantibody production dependent on IDO2’s non-enzymatic function. We propose that this differential use of non- enzymatic vs. enzymatic IDO2 pathways can be specifically targeted as a therapeutic strategy to inhibit IDO2 function in autoimmune responses without affecting its role in protective immunity. In this proposal, we will use preclinical models of autoimmune arthritis, IDO2 and Runx1 conditional knockout mice and overexpressing cell lines, and whole transcriptome RNA-seq analysis to define the cellular and molecular mechanism mediating IDO2 non-enzymatic function (Aim 1). We will then use catalytically inactive IDO2 knock- in mice and a novel IDO2-targeting antibody, together with IDO2-dependent models of autoimmunity and protective immunity, to determine if differential use of non-enzymatic vs. enzymatic pathways distinguishes IDO2 function in autoimmune and protective immune responses (Aim 2). The potential long-term impact of this project would move targeting non-enzymatic IDO2 function into development as a novel strategy to treat autoantibody-mediated autoimmune diseases.
