The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation

By Ruoning Wang, C. Dillon, L. Shi, S. Milasta, Robert A. Carter, D. Finkelstein, L. McCormick, Patrick Fitzgerald, Hongbo Chi, Joshua C. Munger and 1 more. Immunity, 2011

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SUMMARY 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.

Subfields: Cancer Research, Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/875ab8e004ff0b7302f79cb110240f0aca120878

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Citations in the corpus

Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses (2015, background): “Additionally, treating TH1 CD4+ T cells with PKM2activatorDASS,whichwill decrease intracellularPEP levels (data not shown) (Anastasiou et al., 2012), similarly suppressed the production of IFNg and CD40L (Figure S5C).”
Foxp3 reprograms T cell metabolism to function in low glucose high lactate environments (2017, background): “Myc is a transcription factor that has important roles in upregulating glycolysis and glutaminolysis in activated T cells (Wang et al., 2011).”
Unraveling the Complex Interplay Between T Cell Metabolism and Function (2018, background): “In addition, TCR signals induce c-Myc, which enacts transcription of metabolic genes critical for T cell activation (16).”
MYC on the Path to Cancer (2012, background): “Loss of Myc was associated with profoundly diminished expression of genes involved in metabolism and the inability for normal primary T cells to grow and proliferate (Wang et al., 2011a).”
Regulation of glycolysis by the hypoxia‐inducible factor (HIF): implications for cellular physiology (2020, background): “…including dendritic cells (Krawczyk et al. 2010), classically activated M1 macrophages (Michl et al. 1976), neutrophils (Sbarra & Karnovsky, 1959), lymphocytes (T cells (Frauwirth et al. 2002; Wang et al. 2011) and B cells (Doughty et al. 2006)) adopt a high-glycolytic phenotype once activated.”
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Distinct Regulation of Th17 and Th1 Cell Differentiation by Glutaminase-Dependent Metabolism (2018, background): “In addition to increased use of glucose in activated effector T cells, glutamine uptake andglutaminolysis are also upregulated (Carr et al., 2010; Wang et al., 2011).”
IL-2 modulates the TCR signaling threshold for CD8 but not CD4 T cell proliferation on a single cell level (2017, background): “c-Myc and related PRGs, such as c-Fos and Jun, may collectively enforce such a threshold by directing a broad program of metabolic reprogramming and proliferation (28).”
Memory CD8+ T cells use cell intrinsic lipolysis to support the metabolic programming necessary for development (2014, background): “Importantly, although the data showing that memory T and Tn cells acquire more 2NBDG than Teff are surprising, they do not argue against a role for glucose and glycolysis in Teff cell proliferation or effector function (Chang et al., 2013; Fox et al., 2005; Jacobs et al., 2008; Wang et al., 2011).”
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MYC, metabolism, cell growth, and tumorigenesis. (2013, background): “In certain cell models, resting cells use fatty acid oxidation as a means to generate ATP, maintain membrane potentials, and turn over organelles (Wang et al. 2011).”