Glucose deprivation inhibits multiple key gene expression events and effector functions in CD8+ T cells.
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-gamma 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-gamma 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.
Cham
Candace M
CM
Committee on Cancer Biology, The University of Chicago, Chicago, IL 60637, USA.
Driessens
Gregory
G
O'Keefe
James P
JP
Gajewski
Thomas F
TF
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis* / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D003847:Deoxyglucose / Q000494:pharmacology; D015870:Gene Expression; D020869:Gene Expression Profiling; D005947:Glucose / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D010100:Oxygen / Q000378:metabolism
D016207:Cytokines; D003847:Deoxyglucose; D005947:Glucose; D010100:Oxygen
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