The human immune system has developed an arsenal of highly potent mechanisms for protecting the body from harmful pathogens and neoplastic cells that threaten the health of the organism. However, the same powerful system of defense may become activated against “self” or lose the ability to properly titrate inflammatory responses and thereby cause harmful collateral damage. Despite the presence of physical barriers and developmental immune tolerization, the central nervous system (CNS) acts throughout life as a source of antigens that can induce inappropriate autoreactivity against neuronal and glial proteins. In diseases such as multiple sclerosis (MS) and the autoimmune encephalitides, multiple immune populations are known to mediate aberrant immune activation, yet pathogenic antigen(s) and immune processes remain poorly understood. In MS patients, activated CD8+ cytotoxic T cells are increased in peripheral circulation, infiltrate the brain, and are found in clonally expanded clusters with CNS parenchyma upon autopsy. Furthermore, while a great deal of attention has focused on CD4+ T lymphocytes as contributors to MS pathology, an increased appreciation is emerging for the role of oligoclonal CD8+ T cells in driving progressive neurologic deficit by damaging neurons and their axons. At present, available immunomodulating therapies may reduce the number of clinical relapses and the formation of new demyelinating lesions on imaging studies, yet therapeutic strategies for preventing disease progression in MS and the accumulation of injury remain limited. T cells exhibit profound metabolic reprogramming to fuel the energetic and proliferative demands of activation against autoantigens to support cellular survival, growth, proliferation, and effector functions. Key metabolic pathways upregulated in response to antigenic stimulation include aerobic glycolysis and the pentose phosphate pathway (PPP) as well as increased physiologic reactive oxygen species (ROS)-mediated signaling. Therefore, the overarching hypothesis of this thesis is that PPP inhibition serves as a therapeutically tractable target to limit CD8-mediated disease progression in CNS autoaggressive diseases such as MS. Herein I demonstrate that v peripheral blood cells from MS patients exhibit increased flux through the PPP compared to healthy controls. Additionally, pharmacologic inhibition of the PPP reduces the acquisition of an effector phenotype and suppresses the secretion of proinflammatory cytokines in murine CD8+ T cells. The PPP is engaged by cytoplasmic and mitochondrial ROS production including oxygen species produced from a metabolic mitochondrial mode termed reverse electron transfer (RET). Engagement of the PPP is enhanced by pharmacologic Nrf2 activation, further implicating reactive oxygen species as contributing to PPP-mediated immune activation. Unexpectedly, differential regulation of secreted proinflammatory cytokines suggests that Nrf2-driven PPP flux may shape the acquisition of CD8+ effector phenotype and impact cell survival. Limiting the metabolic flux of glucose-derived metabolites through the PPP rescues neurons from antigenrestricted CD8+ T cell-mediated cytotoxicity and preserves the electrophysiological function of primary neurons expressing cognate antigen. In the myelin oligodendrocyte glycoproteinexperimental autoimmune encephalomyelitis (MOG-EAE) preclinical model of multiple sclerosis, pharmacologic inhibition of the PPP, when administered at the onset of symptoms, is sufficient to delay and ameliorate motor disability. Finally, inhibition of glutathione peroxidase 4 (Gpx4), the enzyme responsible for de-peroxidation of lipids, combined with PPP inhibition prevents propagation of disease conferred by passive transfer of EAE splenocytes to naive animals. Combined Gpx4 and PPP inhibition additionally shape CD8+ phenotypes under conditions of CNS demyelination. These results bolster the potential of immunometabolic therapeutic approaches to limit autoinflammatory and autoimmune injury to preserve neural function in patients with immune-mediated neurologic disease.