title: Adenosine-mono-phosphate-activated protein kinase-independent effects of metformin in T cells.
abstract: The anti-diabetic drug metformin regulates T-cell responses to immune activation and is proposed to function by regulating the energy-stress-sensing adenosine-monophosphate-activated protein kinase (AMPK). However, the molecular details of how metformin controls T cell immune responses have not been studied nor is there any direct evidence that metformin acts on T cells via AMPK. Here, we report that metformin regulates cell growth and proliferation of antigen-activated T cells by modulating the metabolic reprogramming that is required for effector T cell differentiation. Metformin thus inhibits the mammalian target of rapamycin complex I signalling pathway and prevents the expression of the transcription factors c-Myc and hypoxia-inducible factor 1 alpha. However, the inhibitory effects of metformin on T cells did not depend on the expression of AMPK in T cells. Accordingly, experiments with metformin inform about the importance of metabolic reprogramming for T cell immune responses but do not inform about the importance of AMPK.
authors.affiliation: Division of Cell Signalling and Immunology, College of Life Sciences, University of Dundee, Dundee, Scotland, United Kingdom.
authors.forename: Marouan
authors.initials: M
authors.lastname: Zarrouk
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland; School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors.forename: David K
authors.initials: DK
authors.lastname: Finlay
authors.affiliation: Institut Nationale de la Santé et de la Recherche Médicale Unité 1016, Institut Cochin, Paris, France; Centre Nationale de la Recherche Scientifique, Unités Mixtes de Recherche 8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Foretz
authors.affiliation: Institut Nationale de la Santé et de la Recherche Médicale Unité 1016, Institut Cochin, Paris, France; Centre Nationale de la Recherche Scientifique, Unités Mixtes de Recherche 8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.affiliation: Division of Cell Signalling and Immunology, College of Life Sciences, University of Dundee, Dundee, Scotland, United Kingdom.
authors.forename: Doreen A
authors.initials: DA
authors.lastname: Cantrell
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D005947:Glucose / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D046912:Multiprotein Complexes; D008687:Metformin; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose