Posttranscriptional Control of T Cell Effector Function by Aerobic Glycolysis
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SUMMARY A “switch” from oxidative phosphorylation (OXPHOS) to aerobic glycolysis is a hallmark of T cell activation and is thought to be required to meet the metabolic demands of proliferation. However, why proliferating cells adopt this less efficient metabolism, especially in an oxygen-replete environment, remains incompletely understood. We show here that aerobic glycolysis is specifically required for effector function in T cells but that this pathway is not necessary for proliferation or survival. When activated T cells are provided with costimulation and growth factors but are blocked from engaging glycolysis, their ability to produce IFN-γ is markedly compromised. This defect is translational and is regulated by the binding of the glycolysis enzyme GAPDH to AU-rich elements within the 3′ UTR of IFN-γ mRNA. GAPDH, by engaging/disengaging glycolysis and through fluctuations in its expression, controls effector cytokine production. Thus, aerobic glycolysis is a metabolically regulated signaling mechanism needed to control cellular function.
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Post-transcriptional regulation is important in T cell differentiation and function.
“and the importance of post-transcriptional regulation in T cell differentiation and function26.”
From Proteotoxic stress response drives T cell exhaustion and immune evasion (2025) · cites this paper as [26]
The Discussion (p. 10) states that GAPDH posttranscriptionally regulates T cell effector function by reducing cytokine translation. It supports the claim about function, but the passages do not establish a role for post-transcriptional regulation in T cell differentiation. (LLM, conf=0.85)
Experimental — accuracy not yet measuredCancer cells compete with immune cells for glucose uptake (by SLC2A1/GLUT1), produce lactic acid (by LDHA), and generate an acidic extracellular milieu (through the activity of CA9), all of which are immunosuppressive.
“Cancer cells compete with immune cells for glucose uptake (by SLC2A1/GLUT1), produce lactic acid (by LDHA), and generate an acidic extracellular milieu (through the activity of CA9), all of which are immunosuppressive (77–86).”
From HIF inhibitor 32-134D eradicates murine hepatocellular carcinoma in combination with anti-PD1 therapy (2022) · cites this paper as [79]
The coculture results (p. 9) show that lymphoma cells depleted glucose available to CD4 T cells and reduced their IFNγ production. The Introduction (p. 1) says cancer cells can produce lactate through glycolysis, but the Discussion (p. 10) only raises lactate-mediated suppression as a possibility. Our copy does not identify SLC2A1/GLUT1, LDHA, or CA9 in these processes, or establish a CA9-driven acidic extracellular milieu as immunosuppressive. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe glycolytic metabolic pathway promotes IFN-γ expression and T cell effector function.
“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 [24]
Oligomycin blocks expression of early activation markers after TCR ligation and blunts subsequent T cell proliferation.
“Oligomycin, a specific inhibitor of mitochondrial ATP synthase, can block the expression of early activation markers after TCR ligation and blunts subsequent T cell proliferation (27), suggesting that the naïve-to-effector transition requires either de novo production of ATP by mitochondria or specific signals generated during mitochondrial ATP production.”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [27]
GAPDH, by engaging or disengaging the glycolysis pathway and through fluctuations in its expression, regulates the posttranscriptional production of IFN-γ by T cells.
“Lending weight to the REM network hypothesis is a recent study showing that the enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH), by engaging or disengaging the glycolysis pathway and through fluctuations in its expression, regulates the posttranscriptional production of IFN-γ by T cells (27).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [27]
TEFF cells in the tumor microenvironment compete with tumor cells for available glucose, and this competition model of nutrient restriction limits the ability of TEFF cells to produce effector cytokines such as IFN-γ.
“There is evidence that TEFF cells in the tumor microenvironment compete with tumor cells for available glucose, and this competition model of nutrient restriction limits the ability of TEFF cells to produce effector cytokines such as IFN-γ (27).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [27]
Competition between tumor cells and tumor-infiltrating T cells for available glucose can impose nutrient deprivation on TEFF cells that limits their ability to produce effector cytokines.
“Competition between tumor cells and tumor-infiltrating T cells for available glucose can impose nutrient deprivation on TEFF cells that limits their ability to produce effector cytokines (27).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [27]
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- Authors
- Chang, C.-H., Curtis, J. D., Maggi, L. B., Faubert, B., Villarino, A. V., O’Sullivan, D., Huang, S. C.-C., van der Windt, G. J. W., Blagih, J., Qiu, J., Weber, J. D., Pearce, E. J., Jones, R. G., & Pearce, E. L.
- Affiliations
- Washington University in St. Louis (US)
- McGill University (CA)
- National Institutes of Health (US)
- Corresponding author
- Pearce, Erika L.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2013-06
- Volume
- 153
- Issue
- 6
- Pages
- 1239-1251
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3804311
- OpenAlex
- W2146791037
- Semantic Scholar
- 589cec0fc76ff1ac7cc7b633f84ea431e6dd79f6
- Cited by
- 2,204
- References
- 46
- Citations by year
- 2026: 142 · 2025: 180 · 2024: 193 · 2023: 188 · 2022: 232 · 2021: 235 · 2020: 219 · 2019: 176 · 2018: 176 · 2017: 144 · 2016: 128 · 2015: 93 · 2014: 72 · 2013: 23
- FWCI
- 36.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Funders
- McGill University
- National Institutes of Health
- Canadian Institutes of Health Research (MOP-93 799)
- National Cancer Institute (CA158823, CA164062, R21CA158823, R01CA164062)
- National Institute of Allergy and Infectious Diseases (R01AI091965, AI 091965)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- aerobic glycolysis, T cell effector function, post-transcriptional regulation, glyceraldehyde-3-phosphate dehydrogenase, AU-rich elements, IFN-gamma production, oxidative phosphorylation, T cell metabolism, 3' untranslated region, cytokine gene expression, translational regulation
- MeSH terms
- Animals, Glyceraldehyde-3-Phosphate Dehydrogenases, Glycolysis, Interferon-gamma, Listeriosis, Listeria monocytogenes, Lymphocyte Activation, Mice, Inbred C57BL, Oxidative Phosphorylation, T-Lymphocytes, Protein Biosynthesis, 3' Untranslated Regions, Cell Proliferation, Mice
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