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

• Published in: Cell metabolism Vol. 20; no. 1; pp. 61 - 72
• Main Authors: Macintyre, Andrew N., Gerriets, Valerie A., Nichols, Amanda G., Michalek, Ryan D., Rudolph, Michael C., Deoliveira, Divino, Anderson, Steven M., Abel, E. Dale, Chen, Benny J., Hale, Laura P., Rathmell, Jeffrey C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-07-2014
• Subjects: Animals; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - transplantation; Cell Survival; Colitis - immunology; Colitis - metabolism; Colitis - pathology; Glucose - metabolism; Glucose Transporter Type 1 - genetics; Glucose Transporter Type 1 - metabolism; Glucose Transporter Type 3 - genetics; Glucose Transporter Type 3 - metabolism; Glycolysis; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; RNA, Messenger - metabolism; T-Lymphocytes, Helper-Inducer - cytology; T-Lymphocytes, Helper-Inducer - immunology; T-Lymphocytes, Helper-Inducer - metabolism; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Transplantation, Homologous
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2014.05.004

CD4 T cell activation leads to proliferation and differentiation into effector (Teff) or regulatory (Treg) cells that mediate or control immunity. While each subset prefers distinct glycolytic or oxidative metabolic programs in vitro, requirements and mechanisms that control T cell glucose uptake and metabolism in vivo are uncertain. 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 Teff survival and differentiation. Importantly, Glut1 deficiency decreased Teff expansion and the ability to induce inflammatory disease in vivo. Treg cells, in contrast, were enriched in vivo and appeared functionally unaffected 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.
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•CD4 T cells express multiple glucose transporters, including Gluts 1, 3, 6, and 8•Glut1 has nonredundant function in activated, but not resting, CD4 T cells•CD4 Th1 and Th17 selectively require Glut1 in vivo to regulate immunologic diseases•Targeting T cell glucose metabolism in vivo can selectively impact effector cells
T cells undergo distinct metabolic reprogramming events upon activation and differentiation to inflammatory effectors or regulatory cells. Macintyre et al. show that Glut1 is the only glucose transporter required to drive glycolysis for growth and expansion of effector, but not resting or regulatory, CD4 T cells and induce inflammatory diseases.