Inhibition of the Pentose Phosphate Pathway in Cytotoxic T Lymphocytes Preserves Neuronal Function and Ameliorates Neuroinflammatory Disease

Abstract

Abstract In diseases such as multiple sclerosis and autoimmune encephalitides, activated CD8+ cytotoxic T cells infiltrate the brain and are found in clonally expanded clusters that outnumber CD4+ cells in progressive stages of disease. At present, the pathophysiological role of these cells is poorly understood and therapeutic strategies for preventing or ameliorating autoinflammatory disease progression are limited. T cells exhibit profound metabolic reprogramming that facilitates the energetic and proliferative demands of effector T cells. Key metabolic pathways in this reprogramming include upregulation of glycolysis and the pentose phosphate pathway (PPP). Here we show that 1) pharmacologic inhibition of the PPP suppresses effector phenotype acquisition and proinflammatory cytokine secretion by CD8+ T cells; 2) engagement of the PPP is enhanced by pharmacologic Nrf2 activation, implicating reactive oxygen species-induced activation as a transcriptional regulator of PPP-dependent immune activation; 3) Nrf2-driven PPP flux promotes the acquisition of specific CD8+ effector phenotypes; 4) limiting the metabolic flux of glucose-derived metabolites through the PPP prevents CD8+ T cell-mediated injury of neurons expressing cognate antigen and preserves their electrophysiological function; and 5) pharmacologic inhibition of the PPP in B6 mice at symptom onset is sufficient to delay and ameliorate motor disability in the MOG EAE preclinical model of MS. Overall, these results underscore the potential of immunometabolic therapies to limit T cell mediated injury in autoinflammatory and autoimmune diseases across organ systems including the prevention of neurologic deficits in patients with T cell driven neurologic disease. This work was supported by the NIH (R01NS115126 to CLH; T32GM065841 to EMG), the Mayo Clinic Graduate School of Biomedical Sciences, the Mayo Clinic Center for MS and Autoimmune Neurology, and generous donations from Eugene and Marcia Applebaum, Donald J. and Frances I. Herdrich, Bob and Loralee Marvin, and Rob and Debbie Mudge.