Transcription of Il17 and Il17f Is Controlled by Conserved Noncoding Sequence 2

Department of Immunology, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Immunity (Impact Factor: 21.56). 01/2012; 36(1):23-31. DOI: 10.1016/j.immuni.2011.10.019
Source: PubMed


T helper 17 (Th17) cells specifically transcribe the Il17 and Il17f genes, which are localized in the same chromosome region, but the underlying mechanism is unclear. Here, we report a cis element that we previously named conserved noncoding sequence 2 (CNS2) physically interacted with both Il17 and Il17f gene promoters and was sufficient for regulating their selective transcription in Th17 cells. Targeted deletion of CNS2 resulted in impaired retinoic acid-related orphan receptor gammat (RORγt)-driven IL-17 expression in vitro. CNS2-deficient T cells also produced substantially decreased amounts of IL-17F. These cytokine defects were associated with defective chromatin remodeling in the Il17-Il17f gene locus, possibly because of effects on CNS2-mediated recruitment of histone-modifying enzymes p300 and JmjC domain-containing protein 3 (JMJD3). CNS2-deficient animals were also shown to be resistant to experimental autoimmune encephalomyelitis (EAE). Our results thus suggest that CNS2 is sufficient and necessary for Il17 and optimal Il17f gene transcription in Th17 cells.

Download full-text


Available from: Anton M Jetten
  • Source
    • "In addition, NR2F6 also directly competes with the Th17 lineage nuclear orphan receptor RORγt for the DNA accessibility to the hormone response elements within the Il17a conserved noncoding sequences (CNS)2 promoter region (Figure 2) [64,65]. Similar to NR2F6, the nuclear receptors RAR, PPAR, LXR, VDR, GR and ER repress Th17 differentiation and protect against the EAE disease mouse model. "
    [Show abstract] [Hide abstract]
    ABSTRACT: 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 (Ifn) g, Il17 and Il21, 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 RORgammat-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.
    Full-text · Article · Jun 2014 · Cell Communication and Signaling
  • Source
    • "These two cytokines share the strongest sequence homology. The genes encoding IL-17A and IL-17F are close to each other on the same chromosome in both mouse and human, underscoring their shared patterns of expression.1 Functionally, both IL-17A and IL-17F mediate pro-inflammatory responses, with certain differences depending on the type and site of inflammation.2,3 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Interleukin 17 (IL-17) and its closest relative, IL-17F, have recently drawn much attention in the field of immunology. IL-17 and IL-17F are expressed by a distinct type of T cells, T helper 17 cells and certain other lymphocytes. These cytokines play key regulatory roles in host defense and inflammatory diseases. In this review, we summarize the recent findings in IL-17 biology and the progress towards understanding the regulatory mechanisms of IL-17 expression and signaling mechanisms. This knowledge will benefit the development of novel immune modulators that enhance immunity to various infections and reduce inflammatory damage in infected patients.
    Full-text · Article · Sep 2013 · Emerging Microbes and Infections
  • Source
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Aug 2012 · Journal of Autoimmunity
Show more