Abstract
<jats:p><p dir="ltr">Proinflammatory Th1 CD4 T cells orchestrate β-cell destruction in Type 1 diabetes (T1D) by utilizing 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 pre-diabetic 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 pre-diabetic non-obese diabetic (NOD) mice with 2-DG significantly delayed spontaneous T1D compared to 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 <i>IFNG</i> and <i>TBX21</i> 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.</p></jats:p>