Glutamine-dependent α-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation - PubMed (original) (raw)

. 2015 Sep 29;8(396):ra97.

doi: 10.1126/scisignal.aab2610.

Xuguang Tai 2, Philippe A Robert 3, Marco Craveiro 1, Gaspard Cretenet 1, Leal Oburoglu 1, Cédric Mongellaz 1, Stefan Floess 4, Vanessa Fritz 1, Maria I Matias 1, Carmen Yong 5, Natalie Surh 1, Julien C Marie 6, Jochen Huehn 4, Valérie Zimmermann 1, Sandrina Kinet 1, Valérie Dardalhon 7, Naomi Taylor 7

Affiliations

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

Dorota Klysz et al. Sci Signal. 2015.

Abstract

T cell activation requires that the cell meet increased energetic and biosynthetic demands. We showed that exogenous nutrient availability regulated the differentiation of naïve CD4(+) T cells into distinct subsets. Activation of naïve 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 naïve 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.

Copyright © 2015, American Association for the Advancement of Science.

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