Metabolic Profiling Using Stable Isotope Tracing Reveals Distinct Patterns of Glucose Utilization by Physiologically Activated CD8+ T Cells

• Published in: Immunity (Cambridge, Mass.) Vol. 51; no. 5; pp. 856 - 870.e5
• Main Authors: Ma, Eric H., Verway, Mark J., Johnson, Radia M., Roy, Dominic G., Steadman, Mya, Hayes, Sebastian, Williams, Kelsey S., Sheldon, Ryan D., Samborska, Bozena, Kosinski, Penelope A., Kim, Hyeryun, Griss, Takla, Faubert, Brandon, Condotta, Stephanie A., Krawczyk, Connie M., DeBerardinis, Ralph J., Stewart, Kelly M., Richer, Martin J., Chubukov, Victor, Roddy, Thomas P., Jones, Russell G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.11.2019; Elsevier Limited
• Subjects: Animals; Antigens; Bioenergetics; Biosynthesis; Carbon 13; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell culture; Cell differentiation; Cell Proliferation; Effector cells; Energy Metabolism; Environmental impact; Experiments; Gas Chromatography-Mass Spectrometry; Glucose; Glucose - metabolism; Glycolysis; Host-Pathogen Interactions - genetics; Host-Pathogen Interactions - immunology; Influence; Listeria; Lymphocyte Activation - genetics; Lymphocyte Activation - immunology; Lymphocytes; Lymphocytes T; Medical research; Metabolism; Metabolites; Metabolome; Metabolomics - methods; Mice; Nucleotides; Nutrients; Oxidative metabolism; Oxidative Stress; Peptides; Pharmaceuticals; Phenotypes; Proteomics; Pyruvic acid; Serine; Stable isotopes; T cell receptors; Virus Diseases - genetics; Virus Diseases - immunology; Virus Diseases - metabolism; Virus Diseases - virology
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2019.09.003

Naive CD8+ T cells differentiating into effector T cells increase glucose uptake and shift from quiescent to anabolic metabolism. Although much is known about the metabolism of cultured T cells, how T cells use nutrients during immune responses in vivo is less well defined. Here, we combined bioenergetic profiling and 13C-glucose infusion techniques to investigate the metabolism of CD8+ T cells responding to Listeria infection. In contrast to in vitro-activated T cells, which display hallmarks of Warburg metabolism, physiologically activated CD8+ T cells displayed greater rates of oxidative metabolism, higher bioenergetic capacity, differential use of pyruvate, and prominent flow of 13C-glucose carbon to anabolic pathways, including nucleotide and serine biosynthesis. Glucose-dependent serine biosynthesis mediated by the enzyme Phgdh was essential for CD8+ T cell expansion in vivo. Our data highlight fundamental differences in glucose use by pathogen-specific T cells in vivo, illustrating the impact of environment on T cell metabolic phenotypes. [Display omitted] •Developed 13C-infusion method for studying T cell metabolism in vivo•T cell glucose use and bioenergetics differ between cell culture and mouse models•Glucose metabolism in T cells changes dynamically over an immune response•Glucose-dependent serine biosynthesis supports T cell proliferation in vivo Although much is known about the metabolism of cultured T cells, how T cells use nutrients during immune responses in vivo is not well defined. Using 13C-glucose isotope tracing in mice, Ma et al. demonstrate prominent use of glucose for anabolic metabolism by T cells in vivo. This work highlights the importance of studying T cell metabolism in a physiological environment.