The nuclear orphan receptor NR2F6 suppresses lymphocyte activation and T helper 17-dependent autoimmunity.
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.
Hermann-Kleiter
Natascha
N
Department for Medical Genetics, Molecular and Clinical Pharmacology, Medical University Innsbruck, 6020 Innsbruck, Austria.
Gruber
Thomas
T
Lutz-Nicoladoni
Christina
C
Thuille
Nikolaus
N
Fresser
Friedrich
F
Labi
Verena
V
Schiefermeier
Natalia
N
Warnecke
Marei
M
Huber
Lukas
L
Villunger
Andreas
A
Eichele
Gregor
G
Kaminski
Sandra
S
Baier
Gottfried
G
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
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