Nuclear orphan receptor NR2F6 directly antagonizes NFAT and RORγt binding to the Il17a promoter

J Autoimmun. 2012 Dec;39(4):428-40. doi: 10.1016/j.jaut.2012.07.007. Epub 2012 Aug 24.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Binding, Competitive
  • COUP Transcription Factors / deficiency
  • COUP Transcription Factors / genetics
  • COUP Transcription Factors / immunology*
  • DNA / immunology
  • DNA / metabolism
  • Disease Models, Animal
  • Encephalomyelitis, Autoimmune, Experimental / genetics
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Gene Expression Regulation / immunology
  • Interleukin-17 / genetics
  • Interleukin-17 / immunology*
  • Interleukin-17 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NFATC Transcription Factors / genetics
  • NFATC Transcription Factors / immunology*
  • NFATC Transcription Factors / metabolism
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / immunology*
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
  • Protein Binding
  • Repressor Proteins
  • Response Elements / immunology
  • Signal Transduction
  • Th17 Cells / immunology*
  • Th17 Cells / metabolism
  • Th17 Cells / pathology
  • Transcription, Genetic

Substances

  • COUP Transcription Factors
  • Il17a protein, mouse
  • Interleukin-17
  • NFATC Transcription Factors
  • Nr2f6 protein, mouse
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Repressor Proteins
  • DNA