Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system (CNS) that affects over 1 million people in the US. T-cell-driven immunopathology is a central feature of MS and other immune-mediated diseases. As a consequence, the immune regulation of these pathogenic T-cell responses is an important quest in the approach to autoimmunity. We have had a long-standing interest in the immune basis of human multiple sclerosis (MS) and its animal model (EAE). While the pathogenic role of CD4 T-cells is well established in these diseases, there is growing evidence from us and others for a role of CD8 T-cells in these diseases. Through studies in MS and EAE, we have demonstrated the critical disease regulatory role of CD8 T-cells in disease. Similar appreciation for the role of these cells in downregulating other autoimmune diseases has also emerged. We have also shown that the suppressor activity of MS relapse-associated CD8 T-cells can be restored by in vitro pre-treatment with specific cytokines, revealing functional plasticity of these cells and providing a potential avenue for therapeutic intervention. At the same time, it is also becoming clear that severe autoimmune disease is characterized by increased resistance of effector/pathogenic CD4 T-cells to immune regulation. Collectively, these studies underscore the importance of understanding both the biology of CD4 effector T-cell resistance to suppression as well as the intricacies of CD8 suppression and its modulation. Our proposal addresses this poorly understood but fundamental feature of the immune regulatory apparatus, in the context of MS. Our recent studies demonstrate several novel aspects of the CD4-CD8 effector-regulator dynamics and based on these findings, we hypothesize that CD4 T-cells from MS patients have an intrinsically enhanced tendency to develop effector resistance to immune suppression in an inflammatory context, while CD8 T-cells from MS patients have an intrinsically enhanced tendency to develop lower suppressive ability. We also hypothesize that these phenotypes are plastic and can be modulated by appropriate stimuli. To address these hypotheses, we will use a two-pronged approach: (1) We will address the biology and modulation of CD4 resistance in MS to gain direct insights into these processes in the context of autoimmune disease. A part of this aim will also focus on the novel CD4-intrinsic biology of IL-17 cytokines, as demonstrated in our recent publication; and (2) We will also address the biology and modulation of CD8 suppression in MS. These studies will provide important insights into the immune dysregulation that underlies MS pathogenesis, with implications for treatment approaches in MS and multiple other disease settings.

Multiple sclerosis (MS) and other immune-mediated diseases represent a significant healthcare challenge in veterans. In this study, we take our insights gained from years of work and apply them to dissect novel and poorly understood immune processes that underlie MS. In particular, we will focus on the interactions between CD4 effector T cells and their CD8 T-cell immune regulators to gain an understanding about why pathogenic CD4 effector T-cells may become resistant to immune suppression during a relapse of disease and how one can modulate both CD4 and CD8 T-cells to the greatest immune regulatory effect. These studies will allow us to gain a deeper understanding of immune dysregulation, with the goal of generating better immunotherapeutic strategies in the future.