Glucose deprivation inhibits multiple key gene expression events and effector functions in CD8+ T cells

Authors

  • Candace M. Cham,

    1. Committee on Cancer Biology, The University of Chicago, Chicago, IL, USA
    2. Department of Pathology , The University of Chicago, Chicago, IL, USA
    Current affiliation:
    1. Program in Immunology, Stanford University, Stanford, CA 94305, USA
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    • These authors contributed equally to this work.

  • Gregory Driessens,

    1. Department of Pathology , The University of Chicago, Chicago, IL, USA
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    • These authors contributed equally to this work.

  • James P. O'Keefe,

    Corresponding author
    1. Committee on Cancer Biology, The University of Chicago, Chicago, IL, USA
    2. Department of Pathology , The University of Chicago, Chicago, IL, USA
    • Department of Surgery, Section of Urology, University of Chicago, Chicago, IL 60637, USA
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  • Thomas F. Gajewski

    Corresponding author
    1. Committee on Cancer Biology, The University of Chicago, Chicago, IL, USA
    2. Department of Pathology , The University of Chicago, Chicago, IL, USA
    3. Department of Medicine, Section of Hematology/Oncology, The University of Chicago, Chicago, IL, USA
    • 5841 S. Maryland Ave., MC2115 Chicago, IL 60637, USA Fax: +1-773-702-3163
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  • AMPK

    adenosine-monophosphate-activated protein kinase

    cSMAC

    central supramolecular activation cluster

    2-DG

    2-deoxy-D-glucose

    MTOC

    microtubule organizing center

    TMPD

    N, N, N′, N′-tetramethyl-p-phenylenediamine

  • These authors contributed equally to this work.

Abstract

We recently reported that differentiation of CD8+ T cells from the naïve to the effector state involves the upregulation of glucose-dependent metabolism. Glucose deprivation or inhibition of glycolysis by 2-deoxy-D-glucose (2-DG) selectively inhibited production of IFN-γ but not of IL-2. To determine a more global role of glucose metabolism on effector T-cell function, we performed gene array analysis on CD8+ effector T cells stimulated in the presence or absence of 2-DG. We observed that expression of only 10% of genes induced by TCR/CD28 signaling was inhibited by 2-DG. Among these were genes for key cytokines, cell cycle molecules, and cytotoxic granule proteins. Consistent with these results, production of IFN-γ and GM-CSF, cell cycle progression, upregulation of cyclin D2 protein, cytolytic activity, and upregulation of granzyme B protein and also conjugate formation were exquisitely glucose-dependent. In contrast to glucose, oxygen was little utilized by CD8+ effector T cells, and relative oxygen deprivation did not inhibit these CTL functional properties. Our results indicate a particularly critical role for glucose in regulating specific effector functions of CD8+ T cells and have implications for the maintenance of the effector phase of cellular immune responses in target tissue microenvironments such as a solid tumor.

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