Orphan nuclear receptor NR2F6 acts as an essential gatekeeper of Th17 CD4+ T cell effector functions

Cell Communication and Signaling

Review

Natascha Hermann-Kleiter¹  Gottfried Baier¹ 

[1] Department for Pharmacology and Genetics, Translational Cell Genetics, Medical University of Innsbruck, Peter Mayr Str. 1a, A-6020, Innsbruck, Austria;

关键词: Autoimmune disease;    Pro-inflammatory Th17 cells;    Nuclear orphan receptors;    Immune response balance and check;    NR2F-orphan receptor family;    NFAT;    AP-1;    RORγt;    Transcriptional regulation;   

DOI  :  10.1186/1478-811X-12-38

 received in 2014-04-16, accepted in 2014-06-06,  发布年份 2014

来源: Springer

【 摘 要 】

Members of the evolutionarily conserved family of the chicken ovalbumin upstream promoter transcription factor NR2F/COUP-TF orphan receptors have been implicated in lymphocyte biology, ranging from activation to differentiation and elicitation of immune effector functions. In particular, a CD4+ T cell intrinsic and non-redundant function of NR2F6 as a potent and selective repressor of the transcription of the pro-inflammatory cytokines interleukin (Il) 2, interferon y (ifng) and consequently of T helper (Th)17 CD4+ T cell-mediated autoimmune disorders has been discovered. NR2F6 serves as an antigen receptor signaling threshold-regulated barrier against autoimmunity where NR2F6 is part of a negative feedback loop that limits inflammatory tissue damage induced by weakly immunogenic antigens such as self-antigens. Under such low affinity antigen receptor stimulation, NR2F6 appears as a prototypical repressor that functions to “lock out” harmful Th17 lineage effector transcription. Mechanistically, only sustained high affinity antigen receptor-induced protein kinase C (PKC)-mediated phosphorylation has been shown to inactivate NR2F6, thereby displacing pre-bound NR2F6 from the DNA and, subsequently, allowing for robust NFAT/AP-1- and RORγt-mediated cytokine transcription. The NR2F6 target gene repertoire thus identifies a general anti-inflammatory gatekeeper role for this orphan receptor. Investigating these signaling pathway(s) will enable a greater knowledge of the genetic, immune, and environmental mechanisms that lead to chronic inflammation and of certain autoimmune disorders in a given individual.

【 授权许可】

CC BY   
© Hermann-Kleiter and Baier; licensee BioMed Central Ltd. 2014