Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system (CNS). A great deal of our understanding about the immunologic processes that underlie MS derives from studies in its autoimmune animal model, experimental autoimmune encephalomyelitis (EAE). However, the vast majority of studies in EAE and MS have focused on evaluating and targeting CD4+ T cell responses, with the general assumption that these diseases are predominantly Th1/Th17-mediated and Th2/Treg-modulated. Recent reports from others and us indicate that CD8+ T cells play a role in the pathogenesis as well as regulation of autoimmune demyelination. Our recent studies in MS and EAE have provided evidence for a novel and unexpected disease suppressive role for CNS-specific CD8+ T cells and also demonstrated the requirement of CD8+ T cells in mediating effects of glatiramer acetate (GA) immunotherapy. Based on our data, we hypothesize that a subset of autoantigen-specific or GA-induced CD8 T cells form an important arm of immune regulation during autoimmune demyelinating disease. We propose that this process can be harnessed for the development of an effective immunotherapeutic strategy. The experiments proposed in this application will utilize EAE models to address the fundamental cellular and molecular mechanisms of immune modulation by intrinsic and therapeutic CD8 T cells. In addition, the most potent immune suppressive subset of these populations will be defined with the goal of developing a novel adoptive immunotherapeutic approach. We believe that the proposed experiments will provide greater fundamental insights into CD8 T cell-mediated immune regulation and pave the way for newer intervention strategies for this and other immune-mediated diseases.