The Glucose Transporter Glut1 is Selectively Essential for CD4 T Cell Activation and Effector Function

By Andrew N. Macintyre, Valerie A. Gerriets, Amanda G. Nichols, Ryan D. Michalek, Michael C. Rudolph, D. Deoliveira, S. Anderson, E. Dale Abel, Benny J Chen, L. Hale and 1 more. Cell Metabolism, 2014

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SUMMARY CD4 T cell activation leads to rapid proliferation and differentiation into effector (Teff) or regulatory (Treg) cells that mediate or control immunity. While Teff and Treg prefer distinct glycolytic or oxidative metabolic programs in vitro, requirements and mechanisms that control T cell glucose uptake and metabolism in vivo are poorly understood. Despite expression of multiple glucose transporters, Glut1-deficiency selectively impaired metabolism and function of thymocytes and Teff. Resting T cells were normal until activated, when Glut1-deficiency prevented increased glucose uptake and glycolysis, growth, proliferation, and decreased cell survival and Teff differentiation. Importantly, Glut1-deficiency decreased Teff expansion and ability to induce inflammatory disease in vivo. Treg, in contrast, were enriched in vivo and appeared functionally unaffected by Glut1-deficiency and able to suppress Teff irrespective of Glut1 expression. These data show a selective in vivo requirement for Glut1 in metabolic reprogramming of CD4 T cell activation and Teff expansion and survival.

Subfields: Immunology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/9076992dfd4af442aaa70bee6c2bf4d3169d99d6

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Citations in the corpus

Foxp3 reprograms T cell metabolism to function in low glucose high lactate environments (2017, background): “and effector T cells against cancer (Chang et al., 2013, 2015; Ho et al., 2015; Macintyre et al., 2014; Singer et al., 2011) but, based upon the data shown in this work, may leave Treg relatively unscathed and perhaps contribute to the relative dominance of suppressive Tregs in the tumor microenviro”
Glucose Metabolism Regulates T Cell Activation, Differentiation, and Functions (2014, background): “Indeed, recent investigations have demonstrated that Glut1 is a CD4+ T cell activation marker essential for cell growth and proliferation, and HIV infection in vitro (9, 53).”
Unraveling the Complex Interplay Between T Cell Metabolism and Function (2018, background): “After TCR stimulation, mTORC1 and c-Myc promote glucose and amino acid uptake by enhancing expression of Glut1 and CD98.”
The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivo. (2015, background): “Recent work indicates that the development and function of Teff cells in vivo can be influenced by changes in nutrient transport (Macintyre et al., 2014; Nakaya et al., 2014; Sinclair et al., 2013).”
Metabolic Instruction of Immunity (2017, positive): “Glucose deprivation represses Ca2+ signaling, IFN-γ production, cytotoxicity, and motility in T cells and pro-inflammatory functions in macrophages (Cham et al., 2008; Chang et al., 2013; Chang et al., 2015; Macintyre et al., 2014).”
Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses (2015, background): “Moreover, reducing aerobic glycolysis in activated TH1 cells by glucose deprivation or deletion of the glucose transporter 1 (Macintyre et al., 2014) also suppressed ionomycin-induced cytoplasmic Ca2+ accumulation (Figures 3C and 3D).”
Targeting Metabolism to Improve the Tumor Microenvironment for Cancer Immunotherapy. (2020, background): “differentiation from effector T cells to Tregs (Macintyre et al., 2014).”
T cell metabolism drives immunity (2015, result): “Consistent with these observations, T cell specific deletion of Glut1 impairs CD4 T cell activation, clonal expansion, and survival (Macintyre et al., 2014).”
Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism (2016, background): “Email: lim@mskcc.org Consistent with low Glut1 (13) and LDHA expression (fig.”