The nuclear orphan receptor NR2F6 suppresses lymphocyte activation and T helper 17-dependent autoimmunity

Immunity. 2008 Aug 15;29(2):205-16. doi: 10.1016/j.immuni.2008.06.008.


The protein kinase C (PKC) family of serine-threonine kinases plays a central role in T lymphocyte activation. Here, we identify NR2F6, a nuclear zinc-finger orphan receptor, as a critical PKC substrate and essential regulator of CD4(+) T cell activation responses. NR2F6 potently antagonized the ability of T helper 0 (Th0) and Th17 CD4(+) T cells to induce expression of key cytokine genes such as interleukin-2 (IL-2) and IL-17. Mechanistically, NR2F6 directly interfered with the DNA binding of nuclear factor of activated T cells (NF-AT):activator protein 1 (AP-1) but not nuclear factor kappaB (NF-kappa B) and, subsequently, transcriptional activity of the NF-AT-dependent IL-17A cytokine promoter. Consistent with our model, Nr2f6-deficient mice had hyperreactive lymphocytes, developed a late-onset immunopathology, and were hypersusceptible to Th17-dependent experimental autoimmune encephalomyelitis. Our study establishes NR2F6 as a transcriptional repressor of IL-17 expression in Th17-differentiated CD4(+) T cells in vitro and in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmune Diseases / immunology*
  • Autoimmune Diseases / metabolism
  • Autoimmunity / immunology
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • COUP Transcription Factors
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / metabolism*
  • Interleukin-17 / immunology
  • Interleukin-17 / metabolism*
  • Interleukin-2 / immunology
  • Interleukin-2 / metabolism
  • Lymphocyte Activation*
  • Mice
  • Mice, Knockout
  • Protein Kinase C / metabolism*
  • Receptors, Cytoplasmic and Nuclear / deficiency
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Repressor Proteins
  • T-Lymphocytes, Helper-Inducer / immunology*
  • T-Lymphocytes, Helper-Inducer / metabolism
  • Transcription Factor AP-1 / metabolism


  • COUP Transcription Factors
  • DNA-Binding Proteins
  • Interleukin-17
  • Interleukin-2
  • Nr2f6 protein, mouse
  • Receptors, Cytoplasmic and Nuclear
  • Repressor Proteins
  • Transcription Factor AP-1
  • Protein Kinase C