title: The nuclear orphan receptor NR2F6 suppresses lymphocyte activation and T helper 17-dependent autoimmunity.
abstract: 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.
authors.affiliation: Department for Medical Genetics, Molecular and Clinical Pharmacology, Medical University Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Natascha
authors.initials: N
authors.lastname: Hermann-Kleiter
authors.forename: Thomas
authors.initials: T
authors.lastname: Gruber
authors.forename: Christina
authors.initials: C
authors.lastname: Lutz-Nicoladoni
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Thuille
authors.forename: Friedrich
authors.initials: F
authors.lastname: Fresser
authors.forename: Verena
authors.initials: V
authors.lastname: Labi
authors.forename: Natalia
authors.initials: N
authors.lastname: Schiefermeier
authors.forename: Marei
authors.initials: M
authors.lastname: Warnecke
authors.forename: Lukas
authors.initials: L
authors.lastname: Huber
authors.forename: Andreas
authors.initials: A
authors.lastname: Villunger
authors.forename: Gregor
authors.initials: G
authors.lastname: Eichele
authors.forename: Sandra
authors.initials: S
authors.lastname: Kaminski
authors.forename: Gottfried
authors.initials: G
authors.lastname: Baier
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology* / Q000378:metabolism; D015551:Autoimmunity / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D051836:COUP Transcription Factors; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism*; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism*; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D011493:Protein Kinase C / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000378:metabolism*; D012097:Repressor Proteins; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D051836:COUP Transcription Factors; D004268:DNA-Binding Proteins; D020381:Interleukin-17; D007376:Interleukin-2; C484221:Nr2f6 protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D018808:Transcription Factor AP-1; D011493:Protein Kinase C