c-Rel Controls Multiple Discrete Steps in the Thymic Development of Foxp3 CD4 Regulatory T Cells

Centre for Immunology, Burnet Institute, Melbourne, Australia.
PLoS ONE (Impact Factor: 3.23). 10/2011; 6(10):e26851. DOI: 10.1371/journal.pone.0026851
Source: PubMed


The development of natural Foxp3(+) CD4 regulatory T cells (nTregs) proceeds via two steps that involve the initial antigen dependent generation of CD25(+)GITR(hi)Foxp3(-)CD4(+) nTreg precursors followed by the cytokine induction of Foxp3. Using mutant mouse models that lack c-Rel, the critical NF-κB transcription factor required for nTreg differentiation, we establish that c-Rel regulates both of these developmental steps. c-Rel controls the generation of nTreg precursors via a haplo-insufficient mechanism, indicating that this step is highly sensitive to c-Rel levels. However, maintenance of c-Rel in an inactive state in nTreg precursors demonstrates that it is not required for a constitutive function in these cells. While the subsequent IL-2 induction of Foxp3 in nTreg precursors requires c-Rel, this developmental transition does not coincide with the nuclear expression of c-Rel. Collectively, our results support a model of nTreg differentiation in which c-Rel generates a permissive state for foxp3 transcription during the development of nTreg precursors that influences the subsequent IL-2 dependent induction of Foxp3 without a need for c-Rel reactivation.

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    • "Many of the TCR/NF-κB signaling mediators contribute to normal Treg development, namely IKKβ, protein kinase C-θ and components of the CBM (Carma-1/Bcl-10/Malt-1; Card [caspase-recruitment domain]-Maguk [membrane-associated guanylate kinase] protein-1, B cell lymphoma-10, mucosa-associated lymphoid tissue lymphoma translocation gene-1) complex, which functions upstream of IKKβ activation, as well as IκBα, the NF-κB subunit c-Rel [18]–[27] and the atypical IκB protein IkBNS [28]. Importantly, it was shown that NF-κB can directly target Foxp3 gene expression [25], [28]–[31], and c-Rel binding to the Foxp3 promoter as well as to the recently described pioneer element [30] is crucial for initiating Foxp3 expression during Treg development [32]. However, the contribution of NF-κB to the transcriptional regulation of the TSDR is discussed more controversially [32]. "
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    ABSTRACT: Regulatory T cells (Tregs) obtain immunosuppressive capacity by the upregulation of forkhead box protein 3 (Foxp3), and persistent expression of this transcription factor is required to maintain their immune regulatory function and ensure immune homeostasis. Stable Foxp3 expression is achieved through epigenetic modification of the Treg-specific demethylated region (TSDR), an evolutionarily conserved non-coding element within the Foxp3 gene locus. Here, we present molecular data suggesting that TSDR enhancer activity is restricted to T cells and cannot be induced in other immune cells such as macrophages or B cells. Since NF-κB signaling has been reported to be instrumental to induce Foxp3 expression during Treg development, we analyzed how NF-κB factors are involved in the molecular regulation of the TSDR. Unexpectedly, we neither observed transcriptional activity of a previously postulated NF-κB binding site within the TSDR nor did the entire TSDR show any transcriptional responsiveness to NF-κB activation at all. Finally, the NF-κB subunit c-Rel revealed to be dispensable for epigenetic imprinting of sustained Foxp3 expression by TSDR demethylation. In conclusion, we show that NF-κB signaling is not substantially involved in TSDR-mediated stabilization of Foxp3 expression in Tregs.
    Full-text · Article · Feb 2014 · PLoS ONE
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    • "It is important to note that like CARMA1, c-Rel also plays a nonredundant cell intrinsic role in the development of tTreg precursors [18] [35] [52]. It is believed that both CARMA1 and c-Rel deficient Treg precursors have impaired IL-2R signaling [53] [54] and as a consequence fail to efficiently differentiate into Foxp3 + tTregs in response to IL-2 [52]. "
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    ABSTRACT: Regulatory T cells (Tregs) are a subset of CD4 T cells that are key mediators of immune tolerance. Most Tregs develop in the thymus. In this review we summarise recent findings on the role of diverse signalling pathways and downstream transcription factors in thymic Treg development.
    Full-text · Article · Sep 2013 · Clinical and Developmental Immunology
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    ABSTRACT: Nuclear factor kappa B (NFκB) is a dimeric transcription factor comprised of five family members RelA (p65), RelB, c-Rel, p50 and p52. NFκB signalling is complex and controls a myriad of normal cellular functions. However, constitutive or aberrant activation of this pathway is associated with disease progression and cancer in multiple organs. The diverse array of biological responses is modulated by many factors, including the activating stimulus, recruitment of co-regulatory molecules, consensus DNA binding sequence, dimer composition and post-translational modifications. Each subunit has very different biological functions and in the context of disease the individual subunits forming the NFκB dimer can have a profound effect, causing a shift in the balance from normal to pathogenic signalling. Here we discuss the role of c-Rel dependant signalling in normal physiology and its contribution to disease both inside and outside of the immune system.
    No preview · Article · Mar 2012 · The international journal of biochemistry & cell biology
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