Glutamine-dependent α-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation

T cell activation requires that the cell meet increased energetic and biosynthetic demands. We showed that exogenous nutrient availability regulated the differentiation of naive CD4(+) T cells into distinct subsets. Activation of naive CD4(+) T cells under conditions of glutamine deprivation resulted in their differentiation into Foxp3(+) (forkhead box P3-positive) regulatory T (T-reg) cells, which had suppressor function in vivo. Moreover, glutamine-deprived CD4(+) T cells that were activated in the presence of cytokines that normally induce the generation of T helper 1 (T-H(1)) cells instead differentiated into Foxp3(+) Treg cells. We found that alpha-ketoglutarate (alpha KG), the glutamine-derived metabolite that enters into the mitochondrial citric acid cycle, acted as a metabolic regulator of CD4(+) T cell differentiation. Activation of glutamine-deprived naive CD4(+) T cells in the presence of a cell-permeable alpha KG analog increased the expression of the gene encoding the T-H(1) cell-associated transcription factor Tbet and resulted in their differentiation into T-H(1) cells, concomitant with stimulation of mammalian target of rapamycin complex 1 (mTORC1) signaling. Together, these data suggest that a decrease in the intracellular amount of alpha KG, caused by the limited availability of extracellular glutamine, shifts the balance between the generation of T-H(1) and Treg cells toward that of a T-reg phenotype.