Metabolic Blockade of Glycolysis Diminishes Autoreactive CD4 T-Cell Effector Responses in Type 1 Diabetes

Proinflammatory T helper 1 (Th1) CD4 T cells orchestrate β-cell destruction in type 1 diabetes (T1D) by using glycolysis for effector responses. By targeting T-cell metabolism, we may identify novel mechanisms and therapies to effectively delay T cell–mediated autoimmune diseases like T1D. We hypothesized that treatment of prediabetic mice with the glycolysis inhibitor, 2-deoxyglucose (2-DG), during CD4 T-cell activation would diminish proinflammatory Th1 effector responses and delay β-cell destruction. Treatment of prediabetic nonobese diabetic (NOD) mice with 2-DG significantly delayed spontaneous T1D compared with control mice. In addition to suppressing polyclonal T-cell responses in the pancreatic and mesenteric lymph nodes (LN), diminished Th1 effector responses and an increase in anergy was observed in clonal, autoreactive CD4 T cells stimulated with their cognate autoantigen in the presence of 2-DG. A decrease in CD86 expression in antigen-presenting cells treated with 2-DG may partly explain the induction of CD4 T-cell anergy. Peripheral blood mononuclear cells from patients with or without T1D stimulated with α-CD3/α-CD28–containing microbeads exhibited a decrease in IFNG and TBX21 mRNA with 2-DG treatment. Our studies suggest diminishing glycolysis in autoreactive CD4 T cells can decrease Th1 effector responses and promote anergy as a novel strategy to delay autoimmune diabetes. Article Highlights Our goal: limit glycolysis with 2-deoxyglucose (2-DG) in autoreactive CD4 T cells to delay spontaneous type 1 diabetes in NOD mice. Inhibition of glycolysis with 2-DG during autoreactive CD4 T-cell activation and differentiation decreased effector responses (interferon-γ), increased anergic markers (CD73, folate receptor 4), and delayed spontaneous type 1 diabetes in NOD mice. The effects of 2-DG on antigen-presenting cells resulted in a decrease in CD86 expression that may partly explain the induction of anergy. Inhibiting glycolysis is sufficient to diminish autoreactive CD4 T-cell responses and may be therapeutically applicable to other T cell–mediated inflammatory diseases.