title: IL-1β induced HIF-1α inhibits the differentiation of human FOXP3+T cells.
abstract: Differentiation of regulatory Treg (Treg) in the periphery is critical to control inflammatory processes. Although polarization of inducible Treg (iTreg) often occurs in an inflammatory environment, the effects exerted by inflammation on human iTreg differentiation have not been extensively studied. We observed that IL-1β significantly reduced the frequency of FOXP3+T cells under iTreg-polarizing conditions. Mechanistically, we show that IL-1β activated mTORC1 and downstream upregulated hypoxia inducible factor-1 (HIF-1α) expression. Using specific inhibitors, we demonstrated that both steps were critical in the deleterious effect of IL-1β on Treg differentiation. Chemical stabilization of HIF-1α by Dimethyloxalylglycine (DMOG) also significantly impaired iTreg differentiation. Interestingly, while IL-1β-treated cells exhibited only minor changes in metabolism, DMOG treatment decreased iTreg mitochondrial respiration and increased their glycolytic capacity. In conclusion, exposure to inflammatory stimuli profoundly inhibits human Treg differentiation HIF-1α dependent, suggesting that targeting HIF-1α could be a strategy to foster iTreg differentiation in an inflammatory milieu. However, IL-1β deleterious effect does not appear to be completely driven by metabolic changes. These data thus suggest that several mechanisms contribute to the regulation of iTreg differentiation, but the timing and respective requirement for each pathway vary depending on the milieu in which iTreg differentiate.
authors.affiliation: Department of Infectious Diseases and Microbiology, University of Lübeck, Lübeck, Germany.
authors.forename: Lea M
authors.initials: LM
authors.lastname: Feldhoff
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital Research Foundation, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Cesar M
authors.initials: CM
authors.lastname: Rueda
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital Research Foundation, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Moreno-Fernandez
authors.affiliation: Department of Infectious Diseases and Microbiology, University of Lübeck, Lübeck, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Sauer
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital Research Foundation, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Courtney M
authors.initials: CM
authors.lastname: Jackson
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital Research Foundation, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Claire A
authors.initials: CA
authors.lastname: Chougnet
authors.affiliation: Department of Infectious Diseases and Microbiology, University of Lübeck, Lübeck, Germany. Jan.Rupp@uksh.de.
authors.forename: Jan
authors.initials: J
authors.lastname: Rupp
mesh_terms: D000600:Amino Acids, Dicarboxylic / Q000378:metabolism; D015415:Biomarkers; D002454:Cell Differentiation / Q000187:drug effects; D019069:Cell Respiration; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D015870:Gene Expression; D006019:Glycolysis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D016130:Immunophenotyping; D053583:Interleukin-1beta / Q000378:metabolism*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000600:Amino Acids, Dicarboxylic; D015415:Biomarkers; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053583:Interleukin-1beta; D058570:TOR Serine-Threonine Kinases; C040947:oxalylglycine