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The Transcription Factor Myc Controls Metabolic Reprogramming upon T Lymphocyte Activation
Open accessAbstract
To fulfill the bioenergetic and biosynthetic demand of proliferation, T cells reprogram their metabolic pathways from fatty acid β-oxidation and pyruvate oxidation via the TCA cycle to the glycolytic, pentose-phosphate, and glutaminolytic pathways. Two of the top-ranked candidate transcription factors potentially responsible for the activation-induced T cell metabolic transcriptome, HIF1α and Myc, were induced upon T cell activation, but only the acute deletion of Myc markedly inhibited activation-induced glycolysis and glutaminolysis in T cells. Glutamine deprivation compromised activation-induced T cell growth and proliferation, and this was partially replaced by nucleotides and polyamines, implicating glutamine as an important source for biosynthetic precursors in active T cells. Metabolic tracer analysis revealed a Myc-dependent metabolic pathway linking glutaminolysis to the biosynthesis of polyamines. Therefore, a Myc-dependent global metabolic transcriptome drives metabolic reprogramming in activated, primary T lymphocytes. This may represent a general mechanism for metabolic reprogramming under patho-physiological conditions.
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“Transcription factor enrichment analysis73 revealed that formate-induced transcriptional changes were linked with an enrichment in transcription factors regulating proliferation and metabolism (e.g.: Myc, Max, Myb)74, effector function (e.g.: Fos, Rela, Stat1, Cebpb)75–77 as well as differentiation and epigenetic control (e.g.: Ets1, Yy1, Pou2f2)78 (Figure 6M).”
From Exercise-induced microbiota metabolite enhances CD8 T cell antitumor immunity promoting immunotherapy efficacy (2025) · cites this paper as [74]
In the citing paper
“Glutamine anaplerosis is critical for meeting the energetic requirements of proliferative cells, such as T cells during the transition from quiescent naïve T cells to effector cells, and in cancers, particularly with MYC elevation.32,36,37”
From The multifaceted contributions of mitochondria to cellular metabolism (2018) · cites this paper as [36]
In the citing paper
“In addition, catabolic pathways of ATP generation such as fatty acid β-oxidation are actively suppressed (9).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [9]
In the citing paper
“It is important to note that OXPHOS is still engaged in TEFF cells (9); however, the production of lactate from pyruvate by aerobic glycolysis is the dominant pathway of glucose metabolism in TEFF cells.”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [9]
In the citing paper
“TCR-mediated up-regulation of the transcription factors c-Myc (9) and estrogen-related receptor α (ERRα) (10) enhances the expression of genes involved in intermediary metabolism.”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [9]
In the citing paper
“T cell activation promotes a rapid increase in glucose flux through the oxidative PPP (9).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [9]
In the citing paper
“Glutamine transporters (SNAT1 and SNAT2) as well as key glutaminolysis enzymes (GLS, GPT, GOT, and GLUD) are up-regulated early after T cell activation similar to glycolysis genes (7, 9); several groups have correlated these changes in gene expression to enhanced glutaminolytic flux in lymphocytes (9, 53).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [9]
In the citing paper
“Glutamine transporters (SNAT1 and SNAT2) as well as key glutaminolysis enzymes (GLS, GPT, GOT, and GLUD) are up-regulated early after T cell activation similar to glycolysis genes (7, 9); several groups have correlated these changes in gene expression to enhanced glutaminolytic flux in lymphocytes (9, 53).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [9]
In the citing paper
“Hif-1α is not required for the initiation of aerobic glycolysis in activated T cells; instead, c-Myc is uniquely required for this metabolic shift [111].”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [111]
In the citing paper
“Hif-1α is not required for the initiation of aerobic glycolysis in activated T cells; instead, c-Myc is uniquely required for this metabolic shift [111].”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [111]
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Citations
Cites
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BackgroundMethodInfluentialMetabolic Instruction of Immunity
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HIF transcription factors, inflammation, and immunity
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Influentialc-Myc Is a Universal Amplifier of Expressed Genes in Lymphocytes and Embryonic Stem Cells
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BackgroundInhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function
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BackgroundMethodDe novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells
Berod, L., Friedrich, C., Nandan, A., Freitag, J., Hagemann, S., Harmrolfs, K., Sandouk, A., Hesse, C., Castro, C. N., Bähre, H., et al. (2014) · Nature Medicine · doi:10.1038/nm.3704 · Cited by 927
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“In addition, TCR signals induce c-Myc, which enacts transcription of metabolic genes critical for T cell activation (16).”
BackgroundKeeping It All Going—Complement Meets Metabolism
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“Activation of T cells also enhances mitochondrial biogenesis, uptake of amino acids (AAs), and glutaminolysis (66, 67).”
BackgroundDe Novo Epigenetic Programs Inhibit PD-1 Blockade-Mediated T Cell Rejuvenation
Ghoneim, H. E., Fan, Y., Moustaki, A., Abdelsamed, H. A., Dash, P., Dogra, P., Carter, R., Awad, W., Neale, G. A. M., Thomas, P. G., et al. (2017) · Cell · doi:10.1016/j.cell.2017.06.007 · Cited by 808
“…with the cell’s proliferative potential. c-Myc has been shown to be essential for activationinduced metabolic reprogramming and antigen-driven proliferation of naive CD8 T cells (Wang et al., 2011), and our data revealed that the Myc locus acquires an exhaustion-associated de novo DMR (Figure 1I).”
Self-citationAerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism
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BackgroundDimethyl fumarate targets GAPDH and aerobic glycolysis to modulate immunity
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“Transcription factors including Myc (Wang et al., 2011), estrogen-related receptor a (ERRa) (Michalek et al., 2011b), and the liver X receptors (LXRs) (Bensinger et al., 2008) facilitate T cell metabolic reprogramming by enhancing the expression of metabolic genes downstream of TCR signaling, which…”
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Self-citationSerine is an essential metabolite for effector T cell expansion
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CD8+ T cell metabolism in infection and cancer
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“CD4+ T cells from O compared Y subjects produced less lactate 46 Cell Metabolism 32, 44–55, July 7, 2020 and had lower ECAR (Figures 2A–2D and S2A–S2D).”
InfluentialNormalization of CD4 + T cell metabolism reverses lupus
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“The up-regulation of glycolysis results from a transcriptional reprogramming regulated by c-MYC, HIF1a (hypoxia-inducible factor 1a), and ERRa (estrogen-related receptor a) (12, 15, 16).”
BackgroundMetabolic barriers to cancer immunotherapy
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“In this respect, a previous study has implicated c-myc as a major regulator of glucose metabolism in T cells (Wang et al., 2011).”
BackgroundInfluentialRedox regulation of the immune response
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“It occurs in an environment of extreme inflammation and also plays a dominant role in neutrophil autophagy and survival via FAO (2011) [222].”
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BackgroundTargeting glutamine metabolism as a therapeutic strategy for cancer
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“Myc upregulates the rate-limiting enzymes of the PPP, including G6PD and TKT [87].”
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“Metabolic reprogramming in T cells is mediated through the induction of cMyc (5), a well-described regulator of glycolysis, glutaminolysis, and cell growth, together with the PI3K/Akt pathway (2).”
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“Oxidative phosphorylation is the main source of energy for naive T cells, but upon activation, naïve T cells undergo metabolic reprogramming to aerobic glycolysis, also known as the Warburg effect, while simultaneously augmenting glutamine uptake and catabolism to maintain effector T cell fitness and drive differentia…”
BackgroundGlutathione primes t cell metabolism for inflammation
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Transcriptional Control of Dendritic Cell Development
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mTORC1-Dependent Metabolic Reprogramming Is a Prerequisite for NK Cell Effector Function
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“Indeed, the metabolic changes described in this study to accompany NK cell activation are similar to those that occur in proinflammatory effector T cell subsets (2, 3, 26, 27).”
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“The latter showed that MYC-driven glutamine catabolism couples with multiple biosynthetic pathways, especially ornithine and polyamine biosynthesis (28).”
BackgroundMetabolic pathways in T cell activation and lineage differentiation
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Metabolic checkpoints in activated T cells
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Self-citationThe Evasion Mechanisms of Cancer Immunity and Drug Intervention in the Tumor Microenvironment
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Metadata
- Authors
- Wang, R., Dillon, C. P., Shi, L. Z., Milasta, S., Carter, R., Finkelstein, D., McCormick, L. L., Fitzgerald, P., Chi, H., Munger, J., & Green, D. R.
- Affiliations
- St. Jude Children's Research Hospital (US)
- University of Rochester Medicine (US)
- Corresponding author
- Green, Douglas R.
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2011-12
- Volume
- 35
- Issue
- 6
- Pages
- 871-882
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC3248798
- OpenAlex
- W2079999658
- Cited by
- 2,140
- References
- 59
- Citations by year
- 2026: 137 · 2025: 147 · 2024: 168 · 2023: 175 · 2022: 220 · 2021: 203 · 2020: 199 · 2019: 173 · 2018: 158 · 2017: 150 · 2016: 127 · 2015: 99 · 2014: 80 · 2013: 62 · 2012: 37
- FWCI
- 19.59
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Public Health Service (S064599)
- National Institute of General Medical Sciences (R37GM052735, R01GM052735, GM-52735)
- National Institute of Allergy and Infectious Diseases (R01AI040646, R56AI081773, AI081773, R01AI081773, AI40646)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (K01AR053573, AR053573)
- 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 › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- c-Myc, T cell activation, metabolic reprogramming, glycolysis, glutaminolysis, polyamine biosynthesis, HIF-1α, TCA cycle, pentose phosphate pathway, glutamine deprivation, nucleotides, T cell proliferation, transcription factors
- MeSH terms
- Animals, Gene Expression Regulation, Glucose, Glutamine, Lymphocyte Activation, Mice, Inbred C57BL, Ornithine, Polyamines, T-Lymphocytes, Proto-Oncogene Proteins c-myc, Mice, Knockout, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Metabolic Networks and Pathways, TOR Serine-Threonine Kinases, Transcriptome
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