Foxo proteins cooperatively control the differentiation of FOXP3+ regulatory T cells

Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Nature Immunology (Impact Factor: 20). 07/2010; 11(7):618-27. DOI: 10.1038/ni.1884
Source: PubMed


CD4(+) regulatory T cells (T(reg) cells) characterized by expression of the transcription factor Foxp3 have a pivotal role in maintaining immunological tolerance. Here we show that mice with T cell-specific deletion of both the Foxo1 and Foxo3 transcription factors (collectively called 'Foxo proteins' here) developed a fatal multifocal inflammatory disorder due in part to T(reg) cell defects. Foxo proteins functioned in a T(reg) cell-intrinsic manner to regulate thymic and transforming growth factor-beta (TGF-beta)-induced Foxp3 expression, in line with the ability of Foxo proteins to bind to Foxp3 locus and control Foxp3 promoter activity. Transcriptome analyses showed that Foxo proteins regulated the expression of additional T(reg) cell-associated genes and were essential for inhibiting the acquisition of effector T cell characteristics by T(reg) cells. Thus, Foxo proteins have crucial roles in specifying the T(reg) cell lineage.

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    • "This is most likely modulated by the demethylation of the Foxp3 promoter or conserved non-coding regions in the Foxp3 locus (11). In addition, multiple transcription factors, including cAMP response element modulator (CREB)/activating transcription factors (ATF), Ets-1 (protein C-ets-1), forkhead box protein O1 (Foxo1), forkhead box protein O3 (Foxo3), and signal transducer and activator of transcription 5 (STAT5), regulate Foxp3 transcription (12, 13). It is not fully clear whether Foxp3+ Treg cells can lose Foxp3 expression and suppressive function, as well as whether Foxp3+ Treg cells exhibit characteristics of other Th cell subsets. "
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    ABSTRACT: Regulatory T (Treg) cells are essential for normal immune surveillance systems, and their dysfunction leads to development of diseases, such as autoimmune disorders. CD4(+)CD25(+) Treg cells are well-known suppressive cells, which express the transcription factor Foxp3, are indispensable for the maintenance of immune self-tolerance and homeostasis by suppressing aberrant or excessive immune response. Other Foxp3(-) Treg cells include Tr1, Th3, CD8(+)CD28(-/-), and Qa1-restricted T cells; however, the contribution of these Treg cells to self-tolerance, immune homeostasis as well as preventing autoimmunity is not well defined. Here, we discuss the phenotypes and function of Foxp3(+) Treg cells and the potential use of such Treg cells against rheumatoid arthritis (RA). Of note, even though most expanded populations of Foxp3(+) Treg cells exhibit suppressive activity, tissue-associated or antigen-specific Treg cells appear superior in suppressing local autoimmune disorders such as RA. In addition, utilizing tissue-associated Foxp3(+) Treg cells from stem cells may stable Foxp3 expression and avoid induction of a potentially detrimental systemic immunosuppression.
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    • "This seemed to correlate well with the above-mentioned ‘FOXO signature’ discovered with GSEA-MSigDB. FOXO proteins are important for developmental regulation, for example in the differentiation of T-cells to become regulatory T cells [35] (see discussion). "
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    ABSTRACT: A large body of evidence from human and animal studies demonstrates that the maternal diet during pregnancy can programme physiological and metabolic functions in the developing fetus, effectively determining susceptibility to later disease. The mechanistic basis of such programming is unclear but may involve resetting of epigenetic marks and fetal gene expression. The aim of this study was to evaluate genome-wide DNA methylation and gene expression in the livers of newborn rats exposed to maternal protein restriction. On day one postnatally, there were 618 differentially expressed genes and 1183 differentially methylated regions (FDR 5%). The functional analysis of differentially expressed genes indicated a significant effect on DNA repair/cycle/maintenance functions and of lipid, amino acid metabolism and circadian functions. Enrichment for known biological functions was found to be associated with differentially methylated regions. Moreover, these epigenetically altered regions overlapped genetic loci associated with metabolic and cardiovascular diseases. Both expression changes and DNA methylation changes were largely reversed by supplementing the protein restricted diet with folic acid. Although the epigenetic and gene expression signatures appeared to underpin largely different biological processes, the gene expression profile of DNA methyl transferases was altered, providing a potential link between the two molecular signatures. The data showed that maternal protein restriction is associated with widespread differential gene expression and DNA methylation across the genome, and that folic acid is able to reset both molecular signatures.
    Full-text · Article · Dec 2013 · PLoS ONE
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    • "A third, highly conserved, CpG dinucleotide-rich region in both mouse and human Th cells, termed the " Treg-specific demethylated region " (TSDR), is completely demethylated in nTregs, but methylated in conventional T cells (Baron et al., 2007; Floess et al., 2007). In tTregs, this area also contains acetylated histones (H3Ac and H4Ac) (Floess et al., 2007) and TF binding sites, which in the demethylated state bind Stat5, CREB/ATF (Yao et al., 2007; Nagar et al., 2008), Foxo1, and Foxo3 (Ouyang et al., 2010), which also bind the Foxp3 promoter (Harada et al., 2010; Ouyang et al., 2010). Interestingly, Foxp3 induction by TGF-β is associated with only partial demethylation of the TSDR, an unstable state that reverses upon restimulation (Floess et al., 2007). "
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    ABSTRACT: Physiological health must balance immunological responsiveness against foreign pathogens with tolerance toward self-components and commensals. Disruption of this balance causes autoimmune diseases/chronic inflammation, in case of excessive immune responses, and persistent infection/immunodeficiency if regulatory components are overactive. This homeostasis occurs at two different levels: at a resting state to prevent autoimmune disease, as autoreactive effector T-cells (Teffs) are only partially deleted in the thymus, and during inflammation to prevent excessive tissue injury, contract the immune response, and enable tissue repair. Adaptive immune cells with regulatory function ("regulatory T-cells") are essential to control Teffs. Two sets of regulatory T cell are required to achieve the desired control: those emerging de novo from embryonic/neonatal thymus ("thymic" or tTregs), whose function is to control autoreactive Teffs to prevent autoimmune diseases, and those induced in the periphery ("peripheral" or pTregs) to acquire regulatory phenotype in response to pathogens/inflammation. The differentiation mechanisms of these cells determine their commitment to lineage and plasticity toward other phenotypes. tTregs, expressing high levels of IL-2 receptor alpha chain (CD25), and the transcription factor Foxp3, are the most important, since mutations or deletions in these genes cause fatal autoimmune diseases in both mice and men. In the periphery, instead, Foxp3(+) pTregs can be induced from naïve precursors in response to environmental signals. Here, we discuss molecular signatures and induction processes, mechanisms and sites of action, lineage stability, and differentiating characteristics of both Foxp3(+) and Foxp3(-) populations of regulatory T cells, derived from the thymus or induced peripherally. We relate these predicates to programs of cell-based therapy for the treatment of autoimmune diseases and induction of tolerance to transplants.
    Full-text · Article · Jun 2013 · Frontiers in Immunology
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