The DOI matches its Crossref record; 58 of the 59 references it cites were found in a registry or an index.
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
Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation
Vander Heiden, M. G., Cantley, L. C., & Thompson, C. B. (2009) · Science · doi:10.1126/science.1160809 · Cited by 16,197 · cited 2×
“The metabolic changes associated with T cell activation are reminiscent of the characteristic metabolic activities of tumor cells and may represent a general metabolic reprogramming during cell growth and proliferation (Kim and Dang, 2006; Vander Heiden et al., 2009; Warburg, 1956).”
BackgroundCluster analysis and display of genome-wide expression patterns
Eisen, M. B., Spellman, P. T., Brown, P. O., & Botstein, D. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.25.14863 · Cited by 16,184 · cited 1×
“The comparison of cytokine gene expression in resting and active T cells was visualized as heat maps with Cluster (Eisen and Brown, 1999) and TreeView (Eisen et al., 1998).”
MethodWarburg, O. (1956) · Science · doi:10.1126/science.123.3191.309 · Cited by 13,425 · cited 1×
“The metabolic changes associated with T cell activation are reminiscent of the characteristic metabolic activities of tumor cells and may represent a general metabolic reprogramming during cell growth and proliferation (Kim and Dang, 2006; Vander Heiden et al., 2009; Warburg, 1956).”
BackgroundThe Biology of Cancer: Metabolic Reprogramming Fuels Cell Growth and Proliferation
DeBerardinis, R. J., Lum, J. J., Hatzivassiliou, G., & Thompson, C. B. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2007.10.002 · Cited by 4,088 · cited 2×
“Whereas prokaryotes and unicellular eukaryotes rely primarily on homeostatic regulation of cell metabolism, metabolic programs in multicellular eukaryotes have evolved to be actively controlled by extracellular signals (Deberardinis et al., 2008).”
BackgroundArginine metabolism: nitric oxide and beyond
WU, G., & MORRIS, S. M. (1998) · Biochemical Journal · doi:10.1042/bj3360001 · Cited by 2,811
DeBerardinis, R. J., Mancuso, A., Daikhin, E., Nissim, I., Yudkoff, M., Wehrli, S., & Thompson, C. B. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0709747104 · Cited by 2,622 · cited 1×
“Metabolic flux analysis in a glioblastoma cell line further revealed that a major portion of glutamine-derived nitrogen and carbon are incorporated into amino acids and lactate, a fraction of which are secreted as metabolic by-products (DeBerardinis et al., 2007).”
BackgroundGao, P., Tchernyshyov, I., Chang, T.-C., Lee, Y.-S., Kita, K., Ochi, T., Zeller, K. I., De Marzo, A. M., Van Eyk, J. E., Mendell, J. T., et al. (2009) · Nature · doi:10.1038/nature07823 · Cited by 2,124 · cited 3×
“Recent studies in human cell lines have suggested that enforced expression of Myc regulates the rate-limiting glutaminolyic enzyme glutaminase 1 (Gls1) through both transcription and posttranscriptional mechanisms (Gao et al., 2009; Wise et al., 2008), and p53 regulates the transcription of glutaminase 2 (Gls2) (Hu et…”
BackgroundTumor spectrum analysis in p53-mutant mice
Jacks, T., Remington, L., Williams, B. O., Schmitt, E. M., Halachmi, S., Bronson, R. T., & Weinberg, R. A. (1994) · Current Biology · doi:10.1016/s0960-9822(00)00002-6 · Cited by 2,051 · cited 2×
“Animals Hif1a and p53-null mice on the C57BL/6 background were purchased from the Jackson Laboratory (Jacks et al., 1994; Ryan et al., 2000) and Hif1a mice were crossed with ROSA26CreERT2 (de Luca et al.”
MethodWise, D. R., DeBerardinis, R. J., Mancuso, A., Sayed, N., Zhang, X.-Y., Pfeiffer, H. K., Nissim, I., Daikhin, E., Yudkoff, M., McMahon, S. B., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0810199105 · Cited by 2,001 · cited 4×
“Because a-KG is required to maintain cell viability and minimal cell proliferation in the absence of glutamine (Wise et al., 2008), addition of a-KG alone was sufficient to drive only one cell division in the absence of glutamine.”
BackgroundInfluentialShi, L. Z., Wang, R., Huang, G., Vogel, P., Neale, G., Green, D. R., & Chi, H. (2011) · Journal of Experimental Medicine · doi:10.1084/jem.20110278 · Cited by 1,803 · cited 1×
“To further test the dependency of T cell proliferation on glucose and glutamine catabolism in vivo, we applied 2DG and DON in an adoptive transfer model by using ovalbumin (OVA)specific, TCR-transgenic OT-II T cells (Figure 1G; Shi et al., 2011).”
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Wu, J., Kakoola, D. N., Lenchik, N. I., Desiderio, D. M., Marshall, D. R., & Gerling, I. C. (2012) · PLoS ONE · doi:10.1371/journal.pone.0046941 · Cited by 31
TCR-signaling events in cellular metabolism and specialization
Chisolm, D. A., & Weinmann, A. S. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00292 · Cited by 26
“the activation of the lipid biosynthesis pathway, are required for robust proliferation and effector T cell differentiation (12, 13).”
BackgroundInfluentialWang, Y., Ju, X., Hua, R., Chen, J., Dai, X., Liu, L., Wang, G., Bai, Y., Hu, H., & Li, X. (2024) · British Journal of Cancer · doi:10.1038/s41416-024-02856-8 · Cited by 18
“In summary, our results demonstrate that the application of deep learning to routine histology may provide prognostic imaging biomarkers to advance personalised immunotherapy for lung cancer.”
Li, C., Qin, C., Li, X., Wang, J., Li, Y., & Sun, Q. (2026) · International Journal of Oncology · doi:10.3892/ijo.2026.5845 · Cited by 3
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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