title: Complement Regulates Nutrient Influx and Metabolic Reprogramming during Th1 Cell Responses.
abstract: Expansion and acquisition of Th1 cell effector function requires metabolic reprogramming; however, the signals instructing these adaptations remain poorly defined. Here we found that in activated human T cells, autocrine stimulation of the complement receptor CD46, and specifically its intracellular domain CYT-1, was required for induction of the amino acid (AA) transporter LAT1 and enhanced expression of the glucose transporter GLUT1. Furthermore, CD46 activation simultaneously drove expression of LAMTOR5, which mediated assembly of the AA-sensing Ragulator-Rag-mTORC1 complex and increased glycolysis and oxidative phosphorylation (OXPHOS), required for cytokine production. T cells from CD46-deficient patients, characterized by defective Th1 cell induction, failed to upregulate the molecular components of this metabolic program as well as glycolysis and OXPHOS, but IFN-γ production could be reinstated by retrovirus-mediated CD46-CYT-1 expression. These data establish a critical link between the complement system and immunometabolic adaptations driving human CD4(+) T cell effector function.
authors.affiliation: Division of Transplant Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Kolev
authors.affiliation: Department of Biomedicine, Immunobiology, University of Basel, 20 Hebelstrasse, 4031 Basel, Switzerland.
authors.forename: Sarah
authors.initials: S
authors.lastname: Dimeloe
authors.affiliation: Division of Transplant Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
authors.forename: Gaelle
authors.initials: G
authors.lastname: Le Friec
authors.affiliation: Department of Dermatology, University Hospital Zurich, 31 Gloriastrasse, 8091 Zürich, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Navarini
authors.affiliation: Division of Transplant Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Arbore
authors.affiliation: Division of Transplant Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK; Biomedical Research Centre, King's Health Partners, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
authors.forename: Giovanni A
authors.initials: GA
authors.lastname: Povoleri
authors.affiliation: Department of Biomedicine, Immunobiology, University of Basel, 20 Hebelstrasse, 4031 Basel, Switzerland.
authors.forename: Marco
authors.initials: M
authors.lastname: Fischer
authors.affiliation: Department of Biomedicine, Immunobiology, University of Basel, 20 Hebelstrasse, 4031 Basel, Switzerland.
authors.forename: Réka
authors.initials: R
authors.lastname: Belle
authors.affiliation: Department of Biomedicine, Immunobiology, University of Basel, 20 Hebelstrasse, 4031 Basel, Switzerland.
authors.forename: Jordan
authors.initials: J
authors.lastname: Loeliger
authors.affiliation: Department of Biomedicine, Immunobiology, University of Basel, 20 Hebelstrasse, 4031 Basel, Switzerland.
authors.forename: Leyla
authors.initials: L
authors.lastname: Develioglu
authors.affiliation: Department of Biomedicine, Immunobiology, University of Basel, 20 Hebelstrasse, 4031 Basel, Switzerland.
authors.forename: Glenn R
authors.initials: GR
authors.lastname: Bantug
authors.affiliation: MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, King's College London, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
authors.forename: Julie
authors.initials: J
authors.lastname: Watson
authors.affiliation: Nephrology Transplantation, CHU Bordeaux, Hospital Pellegrin, CNRS UMR 1564, 146 rue Leo Saignat, 33076 Bordeaux, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Couzi
authors.affiliation: Division of Transplant Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK; Biomedical Research Centre, King's Health Partners, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK; Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA.
authors.forename: Behdad
authors.initials: B
authors.lastname: Afzali
authors.affiliation: MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, King's College London, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Lavender
authors.affiliation: Department of Biomedicine, Immunobiology, University of Basel, 20 Hebelstrasse, 4031 Basel, Switzerland. Electronic address: chess@uhbs.ch.
authors.forename: Christoph
authors.initials: C
authors.lastname: Hess
authors.affiliation: Division of Transplant Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK. Electronic address: claudia.kemper@kcl.ac.uk.
authors.forename: Claudia
authors.initials: C
authors.lastname: Kemper
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D065150:Cellular Reprogramming / Q000276:immunology; D003165:Complement System Proteins / Q000276:immunology*; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D006019:Glycolysis; D006463:Hemolytic-Uremic Syndrome / Q000276:immunology*; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics; D007371:Interferon-gamma / Q000378:metabolism; D027283:Large Neutral Amino Acid-Transporter 1 / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051916:Membrane Cofactor Protein / Q000235:genetics / Q000378:metabolism*; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D010085:Oxidative Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D000076205:Ras Homolog Enriched in Brain Protein; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D018417:Th1 Cells / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051272:Glucose Transporter Type 1; D018398:Homeodomain Proteins; C110719:LAMTOR5 protein, human; D027283:Large Neutral Amino Acid-Transporter 1; D051916:Membrane Cofactor Protein; D046912:Multiprotein Complexes; D009479:Neuropeptides; C490211:RHEB protein, human; D034741:RNA, Small Interfering; D000076205:Ras Homolog Enriched in Brain Protein; C064658:RAG-1 protein; D007371:Interferon-gamma; D003165:Complement System Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins