The mechanisms governing CD4+ T cell activation and function in autoimmune disease remain insufficiently understood even though autoreactive CD4+ T cells are central orchestrators for the initiation and progression of virtually all autoimmune diseases. Multiple sclerosis (MS), a demyelinating disease of the central nervous system (CNS), is a well characterized example of how the failure to control autoreactive CD4+ T cells can lead to devastating inflammation and tissue damage. Encephalitogenic CD4+ T helper (Th) cells, especially Th17 and Th1 cells, promote CNS inflammation by responding to self-antigens both in MS and the murine MS model, experimental autoimmune encephalomyelitis (EAE). Our seminal work has identified an innate-like receptor with critical roles in driving the pathogenicity of encephalitogenic Th17 cells in vivo. Since, we have further identified key transcriptional and epigenetic mechanisms associated with this pathway, indicating that innate-like signaling drives signature programming events that render Th17 cells altogether more pathogenic for autoimmune inflammation. Our preliminary work presented herein demonstrates that activation of this pathway amplifies gene-promoting chromatin modifications at Th17-related loci, likely resulting in increased access for pro-inflammatory transcription factors as well as the binding of a novel chromatin regulatory factor. This chromatin regulator was recently characterized by our laboratory and we demonstrate its essentiality in mediating Th17 cell- dependent autoimmune inflammation. Finally, our data demonstrates that endogenous ligands are potent amplifiers of this pathway as well as encephalitogenicity in Th17 cells. Taken together, these novel results suggest that autoimmune disorders may be treated through targeting the downstream effects of this pathway to inhibit Th17 cells. Therefore, the goal of these studies is to characterize the mechanisms responsible for the increased inflammatory potential that we have firmly established in these Th17 cells. Transcriptional, epigenetic, and functional analyses will be performed to tease out the contributions of the novel regulatory factors identified by our preliminary work. Consequently, our project is designed to test our central hypothesis through two interlinked specific aims.
In this project we will investigate novel mechanisms that contribute to T cell-mediated inflammation in murine models of autoimmune disease. Our previous work has demonstrated that an innate-like receptor expressed by T cells is sufficient to induce inflammatory T cell function. Thus, the goal of this proposal is to understand the pathogenic mechanisms underlying activation of this receptor in T cells.
