title: Metabolic control of type 1 regulatory T cell differentiation by AHR and HIF1-α.
abstract: Our understanding of the pathways that regulate lymphocyte metabolism, as well as the effects of metabolism and its products on the immune response, is still limited. We report that a metabolic program controlled by the transcription factors hypoxia inducible factor-1α (HIF1-α) and aryl hydrocarbon receptor (AHR) supports the differentiation of type 1 regulatory T cell (Tr1) cells. HIF1-α controls the early metabolic reprograming of Tr1 cells. At later time points, AHR promotes HIF1-α degradation and takes control of Tr1 cell metabolism. Extracellular ATP (eATP) and hypoxia, linked to inflammation, trigger AHR inactivation by HIF1-α and inhibit Tr1 cell differentiation. Conversely, CD39 promotes Tr1 cell differentiation by depleting eATP. CD39 also contributes to Tr1 suppressive activity by generating adenosine in cooperation with CD73 expressed by responder T cells and antigen-presenting cells. These results suggest that HIF1-α and AHR integrate immunological, metabolic and environmental signals to regulate the immune response.
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Ivan D
authors.initials: ID
authors.lastname: Mascanfroni
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Maisa C
authors.initials: MC
authors.lastname: Takenaka
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Ada
authors.initials: A
authors.lastname: Yeste
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Bonny
authors.initials: B
authors.lastname: Patel
authors.affiliation: Division of Gastroenterology, Hepatology and Transplantation, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Kenison
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Shafiuddin
authors.initials: S
authors.lastname: Siddiqui
authors.affiliation: Department of Microbiology, Immunology and Parasitology, Escola Paulista de Medicina, Federal University of São Paulo, São Paulo, Brazil.
authors.forename: Alexandre S
authors.initials: AS
authors.lastname: Basso
authors.affiliation: Division of Gastroenterology, Hepatology and Transplantation, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Leo E
authors.initials: LE
authors.lastname: Otterbein
authors.affiliation: Immunology and Hematopoiesis Division, Department of Oncology and Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Drew M
authors.initials: DM
authors.lastname: Pardoll
authors.affiliation: Immunology and Hematopoiesis Division, Department of Oncology and Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Pan
authors.affiliation: Department of Physics, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Avner
authors.initials: A
authors.lastname: Priel
authors.affiliation: Center for Proteomics, The Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Clary B
authors.initials: CB
authors.lastname: Clish
authors.affiliation: Division of Gastroenterology, Hepatology and Transplantation, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Robson
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Quintana
mesh_terms: D000328:Adult; D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D001081:Apyrase / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D005260:Female; D006410:Hematopoiesis / Q000276:immunology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007111:Immunity, Cellular; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018336:Receptors, Aryl Hydrocarbon; D001081:Apyrase; C067869:CD39 antigen