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Rapid effector function of memory CD8+ T cells requires an immediate-early glycolytic switch

Nature Immunology volume 14, pages 1064–1072 (2013)Cite this article

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Abstract

Antigen-experienced memory T cells acquire effector function with innate-like kinetics; however, the metabolic requirements of these cells are unknown. Here we show that rapid interferon-γ (IFN-γ) production of effector memory (EM) CD8+ T cells, activated through stimulation mediated by the T cell antigen receptor (TCR) and the costimulatory receptor CD28 or through cognate interactions, was linked to increased glycolytic flux. EM CD8+ T cells exhibited more glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity at early time points, before proliferation commenced, than did naive cells activated under similar conditions. CD28 signaling via the serine-threonine kinase Akt and the metabolic-checkpoint kinase mTORC2 was needed to sustain TCR-mediated immediate-early glycolysis. Unlike glycolysis in proliferating cells, immediate-early glycolysis in memory CD8+ T cells was rapamycin insensitive. Thus, CD8+ memory T cells have an Akt-dependent 'imprinted' glycolytic potential that is required for efficient immediate-early IFN-γ recall responses.

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Figure 1: Naive and EM CD8+ T cells display distinct oxidative and glycolytic capacities.
Figure 2: The activation-induced immediate-early glycolytic switch is intrinsic to EM CD8+ T cells.
Figure 3: The immediate-early glycolytic switch in EM CD8+ T cells is insensitive to inhibition of mTORC1 but is dependent on Akt activity.
Figure 4: The immediate-early glycolytic switch is dependent on mTORC2 signaling.
Figure 5: IFN-γ synthesis by EM CD8+ T cells is dependent on immediate-early glycolysis.
Figure 6: The immediate-early glycolytic switch is a common feature of memory CD8+ T cell subpopulations.
Figure 7: IFN-γ production by EBV-specific memory CD8+ T cells is diminished in the presence of 2-DG.
Figure 8: Chromatin remodeling of the IFNG promoter in EM CD8+ T cells.

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Acknowledgements

We thank E. Palmer and J.A. Schifferli for discussion of data; E. Traunecker and T. Krebs for technical support with cell sorting; B. Erne for help with imaging; A. Buser (University Hospital Basel) for buffy coats; and M. Stern for statistical help. Supported by the Swiss National Science Foundation (31003A_135677 to C.H., 323630-128881 to P.M.G. and 323530-139181 to M.F.) and Roche (S.D.).

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  1. Patrick M Gubser and Glenn R Bantug: These authors contributed equally to this work.

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  1. Department of Biomedicine, Immunobiology, University of Basel, Basel, Switzerland

    Patrick M Gubser, Glenn R Bantug, Leyla Razik, Marco Fischer, Sarah Dimeloe, Gideon Hoenger, Bojana Durovic, Annaïse Jauch & Christoph Hess

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Contributions

P.M.G. designed, did and analyzed most experiments; G.R.B. designed, did and analyzed experiments and helped write the manuscript; L.R., M.F., S.D., A.J., B.D. and G.H. designed, did and analyzed experiments; and C.H. initiated and oversaw the study, analyzed data and wrote the manuscript.

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Correspondence to Christoph Hess.

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Gubser, P., Bantug, G., Razik, L. et al. Rapid effector function of memory CD8+ T cells requires an immediate-early glycolytic switch. Nat Immunol 14, 1064–1072 (2013). https://doi.org/10.1038/ni.2687

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