Glucose availability regulates IFN-gamma production and p70S6 kinase activation in CD8+ effector T cells.
Differentiation of CD8+ T cells from the naive to the effector state is accompanied by changes in basal gene expression profiles that parallel the acquisition of effector functions. Among these are metabolism genes, and we now show that 2C TCR transgenic effector CD8+ T cells express higher levels of glycolytic enzymes and display greater glucose uptake, a higher glycolytic rate, and increased lactate production compared with naive cells. To determine whether glucose was required for effector T cell functions, we regulated glucose availability in vitro. Glucose deprivation strongly inhibited IFN-gamma gene expression, whereas IL-2 production was little affected. Inhibition correlated with diminished phosphorylation of p70S6 kinase and eIF4E binding protein 1 and a requirement for de novo protein synthesis, whereas other signaling pathways known to regulate IFN-gamma expression were unaffected. Together, our data reveal that optimal induction of IFN-gamma transcription is a glucose-dependent process, indicate that there are undefined factors that influence IFN-gamma expression, and have implications for regulation of the effector phase of CD8+ T cell responses in tissue microenvironments.
Cham
Candace M
CM
Committee on Cancer Biology, Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
Gajewski
Thomas F
TF
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001483:Base Sequence; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D004247:DNA / Q000235:genetics; D003847:Deoxyglucose / Q000494:pharmacology; D004789:Enzyme Activation; D039642:Eukaryotic Initiation Factors; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis / Q000235:genetics; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics; D007376:Interleukin-2 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; D039642:Eukaryotic Initiation Factors; D007376:Interleukin-2; D010750:Phosphoproteins; D012333:RNA, Messenger; D007371:Interferon-gamma; D004247:DNA; D003847:Deoxyglucose; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D005947:Glucose