| First Author | Klysz D | Year | 2015 |
| Journal | Sci Signal | Volume | 8 |
| Issue | 396 | Pages | ra97 |
| PubMed ID | 26420908 | Mgi Jnum | J:259449 |
| Mgi Id | MGI:6141057 | Doi | 10.1126/scisignal.aab2610 |
| Citation | Klysz D, et al. (2015) Glutamine-dependent alpha-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation. Sci Signal 8(396):ra97 |
| abstractText | 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. |
