Ramirez Hernandez, G.; Bell, M.; Kong, B.; Block, S.; Vander Heiden, M.; Kory, N.

The one-carbon metabolic pathway is essential for proliferating cells and has recently been identified as an immunomodulatory target in CD4+ T cells. However, its role in other immune cell types has not been fully established. We investigated the function of the one-carbon pathway in CD8+ T cells, which are the primary effectors responsible for the destruction of pancreatic beta cells that causes type 1 diabetes. Enzymes involved in the one-carbon pathway, as well as levels of formate, a critical intermediate, were upregulated during CD8+ T-cell activation. Pharmacological inhibition of MTHFD2, a mitochondrial enzyme involved in one-carbon metabolism, suppressed CD8+ T-cell activation, proliferation, and effector function. Mechanistically, this effect was mediated by reduced signaling through KRAS and the mTORC1 downstream targets HIF1a, S6, and STAT3. As previously shown in CD4+ T cells, formate supplementation reversed the effects of MTHFD2 inhibition on activation, proliferation, and function of CD8+ T cells, and prevented the reduction of the TCF1high CD8+ progenitor cell population, which has been shown to drive anti-beta cell autoimmunity. Formate levels were elevated in the immune cells isolated from pancreatic lymph nodes during the insulitis stage in non-obese diabetic mice. Treatment of euglycemic non-obese diabetic mice with an MTHFD2 inhibitor during the insulitis stage delayed CD8+ T-cell infiltration into pancreatic islets and postponed the onset of type 1 diabetes. These findings reveal a new paradigm for preventing and delaying the onset of type 1 diabetes.