Cutting Edge: Distinct Glycolytic and Lipid Oxidative Metabolic Programs Are Essential for Effector and Regulatory CD4+ T Cell Subsets

By Ryan D. Michalek, Valerie A. Gerriets, S. Jacobs, Andrew N. Macintyre, Nancie J. MacIver, Emily F. Mason, S. Sullivan, Amanda G. Nichols, J. Rathmell. Journal of Immunology, 2011

1,964 citations recorded by the source corpus.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/d96729d24c437878941f58eb26d4c1f2f03785c6

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Citations in the corpus

Metabolic Instruction of Immunity (2017, neutral): “Although the metabolic characteristics of other CD4 T cell subsets have been compared (Michalek et al., 2011), little was known about Th9 cell metabolism.”
Regulation of glycolysis by the hypoxia‐inducible factor (HIF): implications for cellular physiology (2020, background): “In activated CD4+ T cells, glycolysis plays a primary role in promoting the activation of effector T cells (Michalek et al. 2011), and downregulating glycolysis by silencing of PFKFB3 in CD4 T cells renders these cells highly susceptible to apoptosis and, counterintuitively, impairs autophagy (Yang…”
The multifaceted role of CD4+ T cells in the regulation of CD8+ T cell memory maturation (2015, positive): “Compared with effector T cells, T Reg cells express lower levels of glucose transporter 1 (GLUT1; also known as SLC2A1) and have higher basal lipid oxidation rates, which suggests that they primarily rely on fatty acid oxidation for their energy requirements 94 .”
Unraveling the Complex Interplay Between T Cell Metabolism and Function (2018, background): “Transforming growth factor beta (TGF-β) signals drive Treg differentiation (136) and activate AMPK (137), which promotes FAO and skews inflammatory Th17 cells toward a Treg phenotype (98, 138).”
Metabolic competition in the tumor microenvironment is a driver of cancer progression (2015, background): “Tregs andM2macrophages, neither of which require aerobic glycolysis but instead use fatty acid oxidation (Huang et al., 2014; Michalek et al., 2011; Vats et al., 2006), may often appear in progressing tumors because they can likely survive in low glucose environments.”
The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivo. (2015, background): “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…”
Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function. (2013, positive): “However, low doses of 2DG have been used to address the role of glycolysis in directing the fate decision of CD4 + Th17 cells versus Foxp3 + Tregs (37, 38).”
HIF1α–dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells (2011, background): “Recently added evidence further suggests that Treg cells preferentially use fatty acids and inhibition of fatty acid -oxidation impairs Treg cell differentiation (Michalek et al., 2011).”
Lactate: a metabolic key player in cancer. (2011, background): “In contrast, regulatory T cells (Treg) do not appear to be affected by the presence of lactate and an acidic microenvironment, because they have a different energy metabolism that relies on fatty acid oxidation (19).”
Targeting Metabolism to Improve the Tumor Microenvironment for Cancer Immunotherapy. (2020, background): “High glucose consumption in the TME that exceeds the vascular exchange capacity may promote AMPK activation, which may aid the persistence of suppressive immune cells including TAMs, MDSCs, and Tregs (Blagih et al., 2015; Eichner et al., 2019; Michalek et al., 2011; Siska & Rathmell, 2015).”
Glutamine: Metabolism and Immune Function, Supplementation and Clinical Translation (2018, background): “In contrast, the AMPK pathway inhibits mTOR by suppressing the signalling of this protein and promotes activation of mitochondrial oxidative metabolism rather than the glycolytic pathway [132,133].”
Foxp3 reprograms T cell metabolism to function in low glucose high lactate environments (2017, background): “In contrast, Tregs are less dependent on glycolysis, and they use oxidative phosphorylation (OXPHOS) for their energy production (Gerriets et al., 2015; Michalek et al., 2011).”
Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation. (2015, positive): “While Tregs have high rates of lipid oxidation (13), mitochondrial oxidation of pyruvate has not been previously examined.”