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Glucose Availability Regulates IFN-γ Production and p70S6 Kinase Activation in CD8+ Effector T Cells
Open accessAbstract
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-γ 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-γ expression were unaffected. Together, our data reveal that optimal induction of IFN-γ transcription is a glucose-dependent process, indicate that there are undefined factors that influence IFN-γ expression, and have implications for regulation of the effector phase of CD8+ T cell responses in tissue microenvironments.
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“It is known that the glycolytic metabolic pathway promotes IFN-γ expression and T cell effector function20,24–27.”
From Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer (2021) · cites this paper as [27]
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“Limiting glucose levels leads to cellular competition; this impairs T‐cell function via decreased mTOR signaling.”
From Tumor microenvironment signaling and therapeutics in cancer progression (2023) · cites this paper as [229]
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“Reduction in mTOR activity diminishes IFNγ transcripts in T cells, mitigating Th1 CD4+ T cell differentiation [227, 228, 229].”
From Tumor microenvironment signaling and therapeutics in cancer progression (2023) · cites this paper as [229]
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Metadata
- Authors
- Cham, C. M., & Gajewski, T. F.
- Affiliations
- University of Chicago (US)
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2005-04
- Volume
- 174
- Issue
- 8
- Pages
- 4670-4677
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W1853287186
- Cited by
- 359
- References
- 47
- Citations by year
- 2026: 11 · 2025: 28 · 2024: 32 · 2023: 32 · 2022: 29 · 2021: 28 · 2020: 34 · 2019: 21 · 2018: 21 · 2017: 18 · 2016: 18 · 2015: 14 · 2014: 18 · 2013: 9 · 2012: 13
- FWCI
- 1.89
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (R01AI047919, 1R01AI47919)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- glucose availability, glucose deprivation, IFN-gamma production, p70 S6 kinase, CD8+ effector T cells, T cell metabolism, glycolysis, glucose uptake, lactic acid production, eIF4E-binding protein 1, de novo protein synthesis, interleukin-2, T cell differentiation
- MeSH terms
- Animals, Base Sequence, Carrier Proteins, Deoxyglucose, DNA, Enzyme Activation, Gene Expression Regulation, Glucose, Glycolysis, Interferon-gamma, Interleukin-2, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Transgenic, Phosphoproteins, Phosphorylation, RNA, Messenger, Signal Transduction, Up-Regulation, Mice, Knockout, CD8-Positive T-Lymphocytes, Cell Cycle Proteins, Ribosomal Protein S6 Kinases, 70-kDa, Eukaryotic Initiation Factors, Adaptor Proteins, Signal Transducing, Mice, In Vitro Techniques
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