Research ArticleImmunology

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

See allHide authors and affiliations

Sci. Signal.  29 Sep 2015:
Vol. 8, Issue 396, pp. ra97
DOI: 10.1126/scisignal.aab2610

Feeding immune responses

When a naïve CD4+ T cell is activated by antigen, cytokines determine whether it differentiates into an effector T cell, such as a T helper 1 (TH1) cell, to mount an immune response, or a regulatory T (Treg) cell, which suppresses immune responses. Klysz et al. found that depletion of glutamine from culture medium enhanced the differentiation of naïve CD4+ T cells into Treg cells even in the presence of cytokines that promote TH1 cell generation. Adding a cell-permeable analog of the glutamine-derived metabolite α-ketoglutarate to the glutamine-deprived cells inhibited the generation of Treg cells. Together, these results suggest that glutamine deprivation, which occurs in tumor microenvironments, shifts the balance of the immune response to become more suppressive.


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.

View Full Text