title: Nuclear orphan receptor NR2F6 directly antagonizes NFAT and RORγt binding to the Il17a promoter.
abstract: Interleukin-17A (IL-17A) is the signature cytokine produced by Th17 CD4(+) T cells and has been tightly linked to autoimmune pathogenesis. In particular, the transcription factors NFAT and RORγt are known to activate Il17a transcription, although the detailed mechanism of action remains incompletely understood. Here, we show that the nuclear orphan receptor NR2F6 can attenuate the capacity of NFAT to bind to critical regions of the Il17a gene promoter. In addition, because NR2F6 binds to defined hormone response elements (HREs) within the Il17a locus, it interferes with the ability of RORγt to access the DNA. Consistently, NFAT and RORγt binding within the Il17a locus were enhanced in Nr2f6-deficient CD4(+) Th17 cells but decreased in Nr2f6-overexpressing transgenic CD4(+) Th17 cells. Taken together, our findings uncover an example of antagonistic regulation of Il17a transcription through the direct reciprocal actions of NR2F6 versus NFAT and RORγt.
authors.affiliation: Department for Pharmacology and Genetics, Medical University Innsbruck, Peter Mayr Str. 1a, A-6020 Innsbruck, Austria. natascha.kleiter@i-med.ac.at
authors.forename: Natascha
authors.initials: N
authors.lastname: Hermann-Kleiter
authors.forename: Marlies
authors.initials: M
authors.lastname: Meisel
authors.forename: Friedrich
authors.initials: F
authors.lastname: Fresser
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Thuille
authors.forename: Mathias
authors.initials: M
authors.lastname: Müller
authors.forename: Lukas
authors.initials: L
authors.lastname: Roth
authors.forename: Andreas
authors.initials: A
authors.lastname: Katopodis
authors.forename: Gottfried
authors.initials: G
authors.lastname: Baier
mesh_terms: D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D051836:COUP Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D004247:DNA / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005786:Gene Expression Regulation / Q000276:immunology; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding; D012097:Repressor Proteins; D020218:Response Elements / Q000276:immunology; D015398:Signal Transduction; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D014158:Transcription, Genetic
chemical_list: D051836:COUP Transcription Factors; C098680:Il17a protein, mouse; D020381:Interleukin-17; D050778:NFATC Transcription Factors; C484221:Nr2f6 protein, mouse; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D012097:Repressor Proteins; D004247:DNA