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

Klysz, D.; Tai, X.; Robert, P. A.; Craveiro, M.; Cretenet, G.; Oburoglu, L.; Mongellaz, C.; Floess, S.; Fritz, V.; Matias, M. I.; Yong, C.; Surh, N.; Marie, J. C.; Huehn, J.; Zimmermann, V.; Kinet, S.; Dardalhon, V.; Taylor, N.

Sci Signal

2015 / vol 8 / pages ra97

Abstract

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 (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 alpha-ketoglutarate (alphaKG), 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 alphaKG 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 alphaKG, 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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10.1126/scisignal.aab2610 8/396/ra97 [pii]

1937-9145 (Electronic)

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