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

D Klysz, X Tai, PA Robert, M Craveiro, G Cretenet… - Science …, 2015 - science.org
D Klysz, X Tai, PA Robert, M Craveiro, G Cretenet, L Oburoglu, C Mongellaz, S Floess…
Science signaling, 2015science.org
T cell activation requires that the cell meet increased energetic and biosynthetic demands.
We showed that exogenous nutrient availability regulated the differentiation of naļve CD4+ T
cells into distinct subsets. Activation of naļve CD4+ T cells under conditions of glutamine
deprivation resulted in their differentiation into Foxp3+ (forkhead box P3–positive) regulatory
T (Treg) 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 cell activation requires that the cell meet increased energetic and biosynthetic demands. We showed that exogenous nutrient availability regulated the differentiation of naļve CD4+ T cells into distinct subsets. Activation of naļve CD4+ T cells under conditions of glutamine deprivation resulted in their differentiation into Foxp3+ (forkhead box P3–positive) regulatory T (Treg) 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 (TH1) cells instead differentiated into Foxp3+ Treg cells. We found that α-ketoglutarate (αKG), 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 naļve CD4+ T cells in the presence of a cell-permeable αKG analog increased the expression of the gene encoding the TH1 cell–associated transcription factor Tbet and resulted in their differentiation into TH1 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 αKG, caused by the limited availability of extracellular glutamine, shifts the balance between the generation of TH1 and Treg cells toward that of a Treg phenotype.
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