Epigenetic Control of the foxp3 Locus in Regulatory T Cells

Experimentelle Rheumatologie, Charité Universitaetsmedizin Berlin, Berlin, Germany.
PLoS Biology (Impact Factor: 9.34). 03/2007; 5(2):e38. DOI: 10.1371/journal.pbio.0050038
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Author Summary
Regulatory T cells play a pivotal role in the maintenance of self-tolerance within the immune system by preventing autoimmunity or excessive activation of the T cells that respond to pathogens (naïve and effector T cells). They differentiate within the thymus, but can also be de novo induced in the rest of the body. Mechanisms determining development of a stable regulatory T cell lineage are unknown. Our study provides evidence for a critical role of epigenetic modifications in the locus coding for the forkhead transcription factor Foxp3, which acts as a master switch controlling regulatory T cell development and function: An evolutionarily conserved region within the non-coding part of the gene contains CpG motifs, which are completely demethylated in regulatory T cells, but methylated in naïve and effector T cells, whereas we observed an inverse occurrence of acetylated histones, another epigenetic chromatin modification. Regulatory T cells induced in vitro—which, in contrast to natural regulatory T cells, do not display a stable regulatory T cell phenotype—display only incomplete DNA demethylation despite high Foxp3 expression. Our data suggest that expression of Foxp3 must be stabilized by epigenetic modification to result in a permanent suppressor cell lineage, a finding of significant importance for therapeutic applications involving induction or transfer of regulatory T cells and for the understanding of long-term cell lineage decisions.

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Available from: Edgar Serfling, Oct 05, 2015
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    • "Some mutations in the FOXP3 gene are localized to the intronic region. Although the intronic polymorphism is not in a coding region, it could affect mRNA levels through regulatory functions such as alternative splicing (Moyer et al., 2011) or demethylation of CpG residues in intronic regions of the FOXP3 gene (Floess et al., 2007; Kim and Leonard, 2007; Baron et al., 2007). We investigated two SNPs in the intronic regions, one located in intron 1 (−20A/G (rs2232368)) and the other in intron 9 (+459T/C (rs2280883)). "
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    ABSTRACT: Unexplained recurrent spontaneous abortion (URSA) has been suggested to be associated with the failure of fetal-maternal immunological tolerance in which the regulatory T lymphocytes (Tregs) play a crucial role. This study evaluated the association between single-nucleotide polymorphisms (SNPs) in the forkhead/winged helix transcription factor (FOXP3) gene, a key factor for the development and function of Tregs, and URSA, in an Iranian population. In this case-control study, 195 patients with a history of URSA and101 healthy women were included as case and control groups respectively. Four SNPs in the FOXP3 gene, two in the promoter region: -924A/G and -3279C/A, and two intronic, -20G/A and +459T/C, were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. The -924A/G (p<0.0001) and -20G/A (p=0.008) polymorphisms were found to be associated with URSA. The respective odds ratios (OR) for bearing -924A/G and -20G/A gene polymorphisms were 4.1 [95% CI 2.3-7.5] and 2.1 [95% CI 1.2-3.6] fold higher in URSA women than those in controls. Thus, there were significant differences in the distribution of A and G alleles of -924A/G and -20G/A between URSA and controls (p=0.001, OR; 3.6 [95% CI 2.1-6.1] and p=0.006, OR; 1.6 [95% CI 1-2.6] respectively). No associations were found for -3279C/A and +459T/C polymorphisms between URSA and controls. These results suggest that polymorphisms of the FOXP3 gene might confer susceptibility to URSA, probably by altering FOXP3 function and/or its expression. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Journal of Reproductive Immunology 05/2015; 110. DOI:10.1016/j.jri.2015.04.001 · 2.82 Impact Factor
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    • "The proliferative defect was compounded by increased Treg cell apoptosis, as detected by annexin V staining (Figures S1F and S1G). Analysis of the conserved non-coding region 2 (CNS2) of Foxp3 for epigenetic demethylation, which is normally more pronounced in nTreg cells, revealed its increase in mesenteric Treg cells of sensitized Il4ra F709 mice, consistent with a selective decrease in iTreg cells (Figures S1H and S1I; Floess et al., 2007; Haribhai et al., 2011; Schmitt et al., 2012). The apparent decrease in iTreg cells in allergensensitized Il4ra F709 mice could not be ascribed to deficiency of factors critical for their generation in the SI, including TGF-b1 and the enzyme retinaldehyde dehydrogenase 2 (RALDH-2), given that transcripts encoding both proteins were higher in the SI of sensitized Il4ra F709 mice than in the SI of control mice (Figure S1J). "
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    ABSTRACT: Oral immunotherapy has had limited success in establishing tolerance in food allergy, reflecting failure to elicit an effective regulatory T (Treg) cell response. We show that disease-susceptible (Il4ra(F709)) mice with enhanced interleukin-4 receptor (IL-4R) signaling exhibited STAT6-dependent impaired generation and function of mucosal allergen-specific Treg cells. This failure was associated with the acquisition by Treg cells of a T helper 2 (Th2)-cell-like phenotype, also found in peripheral-blood allergen-specific Treg cells of food-allergic children. Selective augmentation of IL-4R signaling in Treg cells induced their reprogramming into Th2-like cells and disease susceptibility, whereas Treg-cell-lineage-specific deletion of Il4 and Il13 was protective. IL-4R signaling impaired the capacity of Treg cells to suppress mast cell activation and expansion, which in turn drove Th2 cell reprogramming of Treg cells. Interruption of Th2 cell reprogramming of Treg cells might thus provide candidate therapeutic strategies in food allergy. Copyright © 2015 Elsevier Inc. All rights reserved.
    Immunity 03/2015; 42(3). DOI:10.1016/j.immuni.2015.02.004 · 21.56 Impact Factor
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    • "Our previous investigation showed that, among three evolutionarily conserved noncoding sequences (CNSs) located in the Foxp3 intronic regions, CNS2 (also named TSDR for Tregspecific demethylated region) plays a unique role in maintaining Foxp3 expression in mature Treg cells (Zheng et al., 2010). In comparison to other conserved cis-elements in the Foxp3 locus, CNS2 is uniquely enriched with CpG motifs, which are specifically demethylated during thymic Treg cell differentiation (Floess et al., 2007). A number of transcription factors, including CREB, NF-kB, Runx1, STAT5, Gata3, Foxo1, Ets1, and Foxp3 itself, can interact with CNS2, though whether CNS2 plays a nonredundant role for these transcription factors to regulate Foxp3 expression is not clear (Bruno et al., 2009; Kim and Leonard, 2007; Kitoh et al., 2009; Long et al., 2009; Ouyang et al., 2010; Ruan et al., 2009; Rudra et al., 2009; Wang et al., 2011; Wohlfert et al., 2011; Yao et al., 2007). "
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    ABSTRACT: The homeostasis of multicellular organisms requires terminally differentiated cells to preserve their lineage specificity. However, it is unclear whether mechanisms exist to actively protect cell identity in response to environmental cues that confer functional plasticity. Regulatory T (Treg) cells, specified by the transcription factor Foxp3, are indispensable for immune system homeostasis. Here, we report that conserved noncoding sequence 2 (CNS2), a CpG-rich Foxp3 intronic cis-element specifically demethylated in mature Tregs, helps maintain immune homeostasis and limit autoimmune disease development by protecting Treg identity in response to signals that shape mature Treg functions and drive their initial differentiation. In activated Tregs, CNS2 helps protect Foxp3 expression from destabilizing cytokine conditions by sensing TCR/NFAT activation, which facilitates the interaction between CNS2 and Foxp3 promoter. Thus, epigenetically marked cis-elements can protect cell identity by sensing key environmental cues central to both cell identity formation and functional plasticity without interfering with initial cell differentiation.
    Cell 08/2014; 158(4):734–748. DOI:10.1016/j.cell.2014.07.030 · 32.24 Impact Factor
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