title: HIF-1α- and hypoxia-dependent immune responses in human CD4+CD25high T cells and T helper 17 cells.
abstract: The central oxygen sensitive transcription factor HIF-1α has been implicated in the differentiation of n(T(reg)) and Th17 cells and to orchestrate metabolic changes of activated T cells. However, data on the functional relevance of HIF-1α and Hox, in general, for nT(reg)-suppressive activity and T cell function in primary human cells are still missing. Therefore, we analyzed the effect of Hox and HIF-1α on human T(res), n(Treg), and Th17 cells. Under Hox, nT(reg)-mediated suppression of T(res) proliferation, CD25 expression, and secretion of IFN-γ were significantly reduced, whereas expression levels of VEGF, TNF-α, and IL-10 were significantly increased. In contrast to observations in mice, Th17 lineage commitment, as determined by RORγt expression, was not affected by activation or inhibition of HIF-1α expression using DMOG or YC-1 treatment, respectively. Nevertheless, the secretion of IL-17A was increased by DMOG and reduced by YC-1 under Th17-skewing conditions in a dose- dependent manner. In conclusion, Hox and HIF-1α substantially influence human T cell-mediated immune responses by modulation of nT(reg)-suppressive function and IL-17A secretion by Th17 cells.
authors.affiliation: Department of Molecular Biology, University of Geneva, Switzerland; Institute of Medical Microbiology and Hygiene, University of Lübeck, Germany; thomas.bollinger@unige.ch.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bollinger
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Lübeck, Germany;
authors.forename: Sydney
authors.initials: S
authors.lastname: Gies
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Lübeck, Germany;
authors.forename: Julius
authors.initials: J
authors.lastname: Naujoks
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Lübeck, Germany;
authors.forename: Lea
authors.initials: L
authors.lastname: Feldhoff
authors.affiliation: Division of Immunology and Allergy, Department of Medical Specialties, University Hospital and Medical Faculty, Geneva, Switzerland; and.
authors.forename: Annalena
authors.initials: A
authors.lastname: Bollinger
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Lübeck, Germany;
authors.forename: Werner
authors.initials: W
authors.lastname: Solbach
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Lübeck, Germany; Medical Clinic III/Infectious Diseases, University Hospital Schleswig-Holstein/Campus Lübeck, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Rupp
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D020536:Enzyme Activators / Q000494:pharmacology; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000276:immunology*; D007191:Indazoles / Q000494:pharmacology; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D008297:Male; D051379:Mice; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology*
chemical_list: D015704:CD4 Antigens; D016207:Cytokines; D020536:Enzyme Activators; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C508017:IL2RA protein, human; D007191:Indazoles; D053645:Interleukin-2 Receptor alpha Subunit; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole
keywords: DMOG; Th17; Treg; YC-1; cytokines