title: The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivo.
abstract: Naive T cells undergo metabolic reprogramming to support the increased energetic and biosynthetic demands of effector T cell function. However, how nutrient availability influences T cell metabolism and function remains poorly understood. Here we report plasticity in effector T cell metabolism in response to changing nutrient availability. Activated T cells were found to possess a glucose-sensitive metabolic checkpoint controlled by the energy sensor AMP-activated protein kinase (AMPK) that regulated mRNA translation and glutamine-dependent mitochondrial metabolism to maintain T cell bioenergetics and viability. T cells lacking AMPKα1 displayed reduced mitochondrial bioenergetics and cellular ATP in response to glucose limitation in vitro or pathogenic challenge in vivo. Finally, we demonstrated that AMPKα1 is essential for T helper 1 (Th1) and Th17 cell development and primary T cell responses to viral and bacterial infections in vivo. Our data highlight AMPK-dependent regulation of metabolic homeostasis as a key regulator of T cell-mediated adaptive immunity.
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC, H3G 1Y6, Canada; Department of Physiology, McGill University, Montreal, QC, H3G 1Y6, Canada.
authors.forename: Julianna
authors.initials: J
authors.lastname: Blagih
authors.affiliation: Departments of Medicine, Microbiology & Immunology, and Pathology, McGill International TB Centre, McGill University Health Centre and Research Institute, Meakins-Christie Laboratories, Montreal, QC, H2X 2P2, Canada.
authors.forename: François
authors.initials: F
authors.lastname: Coulombe
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC, H3G 1Y6, Canada.
authors.forename: Emma E
authors.initials: EE
authors.lastname: Vincent
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC, H3G 1Y6, Canada; Department of Biochemistry, McGill University, Montreal, QC, H3G 1Y6, Canada.
authors.forename: Fanny
authors.initials: F
authors.lastname: Dupuy
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC, H3G 1Y6, Canada; Department of Biochemistry, McGill University, Montreal, QC, H3G 1Y6, Canada.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Galicia-Vázquez
authors.affiliation: Department of Microbiology and Immunology, McGill University, Montreal, QC, H3A 2B4, Canada; McGill University Health Centre Research Institute, Montreal General Hospital, Montreal, QC, H3G 1A4, Canada.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Yurchenko
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC, H3G 1Y6, Canada; Department of Physiology, McGill University, Montreal, QC, H3G 1Y6, Canada.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Raissi
authors.affiliation: Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
authors.forename: Gerritje J W
authors.initials: GJ
authors.lastname: van der Windt
authors.affiliation: Inserm, U1016, Institut Cochin, Sorbonne Paris Cité, Paris, France, 75014; CNRS, UMR 8104, Sorbonne Paris Cité, Paris, France, 75014; Université Paris Descartes, Sorbonne Paris Cité, Paris, France, 75014.
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.affiliation: Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
authors.forename: Erika L
authors.initials: EL
authors.lastname: Pearce
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC, H3G 1Y6, Canada; Department of Biochemistry, McGill University, Montreal, QC, H3G 1Y6, Canada.
authors.forename: Jerry
authors.initials: J
authors.lastname: Pelletier
authors.affiliation: Department of Microbiology and Immunology, McGill University, Montreal, QC, H3A 2B4, Canada; McGill University Health Centre Research Institute, Montreal General Hospital, Montreal, QC, H3G 1A4, Canada.
authors.forename: Ciriaco A
authors.initials: CA
authors.lastname: Piccirillo
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC, H3G 1Y6, Canada; Department of Microbiology and Immunology, McGill University, Montreal, QC, H3A 2B4, Canada.
authors.forename: Connie M
authors.initials: CM
authors.lastname: Krawczyk
authors.affiliation: Departments of Medicine, Microbiology & Immunology, and Pathology, McGill International TB Centre, McGill University Health Centre and Research Institute, Meakins-Christie Laboratories, Montreal, QC, H2X 2P2, Canada.
authors.forename: Maziar
authors.initials: M
authors.lastname: Divangahi
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC, H3G 1Y6, Canada; Department of Physiology, McGill University, Montreal, QC, H3G 1Y6, Canada. Electronic address: russell.jones@mcgill.ca.
authors.forename: Russell G
authors.initials: RG
authors.lastname: Jones
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000222:Adaptation, Physiological / Q000276:immunology; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D002478:Cells, Cultured; D065150:Cellular Reprogramming / Q000235:genetics / Q000276:immunology; D004734:Energy Metabolism; D005947:Glucose / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D006801:Humans; D056747:Immunomodulation; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics; D055432:Metabolomics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000235:genetics
chemical_list: D005973:Glutamine; C548179:Prkaa1 protein, mouse; D055372:AMP-Activated Protein Kinases; D005947:Glucose