Editors' ChoiceImmunology

Ensuring Effector Function

Science Signaling  25 Jun 2013:
Vol. 6, Issue 281, pp. ec145
DOI: 10.1126/scisignal.2004446

Resting T cells use both aerobic glycolysis and oxidative phosphorylation to generate ATP. To become activated, T cells need to use oxidative phosphorylation for their energy requirements; however, once activated, T cells use aerobic glycolysis even under conditions of sufficient oxygen to support oxidative phosphorylation. It is thought that, although it is a relatively poor generator of ATP, aerobic glycolysis, rather than oxidative phosphorylation, meets the metabolic needs of proliferating T cells. However, Chang et al. found that, once activated, T cells could use either oxidative phosphorylation or aerobic glycolysis to support their proliferation and survival. Replacing glucose in the culture medium with galactose, thus shutting off glycolysis, resulted in the T cells producing less of the effector cytokine interferon-γ (IFN-γ) than was produced by activated T cells that were cultured with glucose. During aerobic glycolysis, the enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH) acts on its substrate glyceraldehyde 3-phosphate (G3P). In addition to functioning in the glycolytic process, GAPDH also binds to the 3′ untranslated region of IFN-γ mRNA. Indeed, Chang et al. found that in activated T cells cultured in galactose, which have reduced G3P abundance, more GAPDH was associated with IFN-γ mRNA than occurred in cells cultured in glucose, an effect that was reversed by the introduction of G3P into the cells. Coculture of activated T cells with EL-4 lymphoma cells resulted in increased glucose consumption by the tumor cells and reduced IFN-γ production by the T cells compared with that in cultures of activated T cells alone. The addition of sufficient glucose to the coculture medium restored IFN-γ production by the T cells. Together, these data suggest that rather than supporting cellular proliferation and survival, aerobic glycolysis is used by activated T cells to ensure optimal IFN-γ production and effector function by alleviating inhibition of IFN-γ translation by GADPH.

C.-H. Chang, J. D. Curtis, L. B. Maggi, B. Faubert, A. V. Villarino, D. O’Sullivan, S. C.-C. Huang, G. J. W. van der Windt, J. Blagih, J. Qiu, J. D. Weber, E. J. Pearce, R. G. Jones, E. L. Pearce, Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 153, 1239–1251 (2013). [PubMed]