FOXP3-mediated inhibition of a global gene regulator is required for maintaining Treg cell commitment
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE16990 | GEO | 2017/05/31
SECONDARY ACCESSION(S): PRJNA117309
REPOSITORIES: GEO
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Project description:Regulatory T (Treg) cells are involved in self tolerance, immune homeostasis, prevention of autoimmunity, and suppression of immunity to pathogens or tumours. The forkhead transcription factor FOXP3 is essential for Treg cell development and function as mutations in FOXP3 cause severe autoimmunity in mice and humans. However, the FOXP3-dependent molecular mechanisms leading to this severe phenotype are not well understood. Here we introduce the chromatin remodelling enzyme SATB1 (special AT-rich sequence-binding protein-1) as an important target gene of FOXP3. So far, SATB1 has been associated with normal thymic T-cell development, peripheral T-cell homeostasis, TH1/TH2 polarization, and reprogramming of gene expression. In natural and induced murine and human FOXP3+ Treg cells SATB1 expression is significantly reduced. While there is no differential epigenetic regulation of the SATB1 locus between Treg and Teffector cells, FOXP3 reduces SATB1 expression directly as a transcriptional repressor at the SATB1 locus and indirectly via miR-155 induction, which specifically binds to the 3’UTR of the SATB1 mRNA. Reduced SATB1 expression in FOXP3+ cells achieved either by overexpression or induction of FOXP3 is linked to significant reduction in TH1 and TH2 cytokines, while loss of FOXP3 function either by knock down or genetic mutation leads to significant upregulation of SATB1 and subsequent cytokine production. Alltogether, these findings demonstrate that reduced SATB1 expression in Treg cells is necessary for maintenance of a Treg-cell phenotype in vitro and in vivo and places SATB1-mediated T cell-specific modulation of global chromatin remodelling central during the decision process between effector and regulatory T-cell function. Gene expression profiling of freshly isolated CD4+ T cells, separated into CD25 negative and positive subpopulations, from three different donors. FOXP3 is stably and constitutively expressed at a high level in CD4+CD25+ regulatory T cells and at a low level in CD4+CD25- cells.
2011-08-13 | E-GEOD-15390 | biostudies-arrayexpress
Project description:Regulatory T (Treg) cells are involved in self tolerance, immune homeostasis, prevention of autoimmunity, and suppression of immunity to pathogens or tumours. The forkhead transcription factor FOXP3 is essential for Treg cell development and function as mutations in FOXP3 cause severe autoimmunity in mice and humans. However, the FOXP3-dependent molecular mechanisms leading to this severe phenotype are not well understood. Here we introduce the chromatin remodelling enzyme SATB1 (special AT-rich sequence-binding protein-1) as an important target gene of FOXP3. So far, SATB1 has been associated with normal thymic T-cell development, peripheral T-cell homeostasis, TH1/TH2 polarization, and reprogramming of gene expression. In natural and induced murine and human FOXP3+ Treg cells SATB1 expression is significantly reduced. While there is no differential epigenetic regulation of the SATB1 locus between Treg and Teffector cells, FOXP3 reduces SATB1 expression directly as a transcriptional repressor at the SATB1 locus and indirectly via miR-155 induction, which specifically binds to the 3’UTR of the SATB1 mRNA. Reduced SATB1 expression in FOXP3+ cells achieved either by overexpression or induction of FOXP3 is linked to significant reduction in TH1 and TH2 cytokines, while loss of FOXP3 function either by knock down or genetic mutation leads to significant upregulation of SATB1 and subsequent cytokine production. Alltogether, these findings demonstrate that reduced SATB1 expression in Treg cells is necessary for maintenance of a Treg-cell phenotype in vitro and in vivo and places SATB1-mediated T cell-specific modulation of global chromatin remodelling central during the decision process between effector and regulatory T-cell function.
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Project description:STAT5 transcription factor activation downstream of the Interleukin-2 receptor (IL-2R) induces expression of Foxp3, a critical step in the differentiation of regulatory T (Treg) cells. Due to the pleiotropic outputs of IL-2R signaling, it is unclear whether STAT5 acts directly on the Foxp3 locus to promote its expression . Here, we report that IL-2 – STAT5 signaling converged on an enhancer (CNS4) during Foxp3 induction. CNS4 facilitated and sustained the IL-2 dependent CD25+Foxp3– precursor to Treg cell transition in the thymus. Its deficiency resulted in markedly impaired Treg cell generation in neonates, which was partially mitigated with age. While the thymic Treg cell paucity caused by CNS4 deficiency did not result in autoimmunity on its own, it exacerbated autoimmune manifestations caused by disruption of the Aire gene. Thus, CNS4 enhancer activity ensures robust Treg cell differentiation early in postnatal life and cooperatively with other tolerance mechanisms, minimizes autoimmunity.
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Project description:The forkhead transcription factor, Foxp3, is pivotal to the development and function of CD4+CD25+ T regulatory (Treg) cells that limit autoimmunity and maintain immune homeostasis. Previous data indicated that many of the functions of Foxp3 are controlled by the acetylation of several lysines within the forkhead domain. We now show that mutation of each of two lysines within the forkhead domain of Foxp3, lysine at position 382 (K17) and lysine at position 393 (K18), impaired Treg suppressive function in vivo and in vitro. Lysine mutations also decreased Treg expression of multiple functionally important Foxp3-regulated genes, and inhibited the promoter remodeling of target genes (CTLA-4 and IL-2) without affecting Foxp3 expression level. These data point to the need for a further understanding of the effects of various post-translational modifications on Foxp3 function. Our studies also provide a rationale for developing small molecule inhibitors of such post-translational modifications so as to regulate Foxp3+ Treg function clinically. RNA from three independent samples from magnetically separated CD4+CD25- T-effector cells transduced with EV, WT-Fopx3, Foxp3-K17R or Foxp3-K18R
2011-02-05 | E-GEOD-27082 | biostudies-arrayexpress
Project description:STAT5 activation downstream of the Interleukin-2 receptor (IL-2R) facilitates Foxp3 expression, which is required for the differentiation and function of regulatory T (Treg) cells. However, due to the pleiotropic roles of IL-2R signaling, it is unclear how STAT5 acts on the Foxp3 locus to promote Treg cell lineage commitment. Here, we report that IL-2–STAT5 signaling converges on an enhancer (CNS4) during early Foxp3 induction. CNS4 facilitates and sustains the IL-2–dependent CD25+Foxp3– precursor to Treg cell transition in the thymus. Its deficiency results in markedly impaired Treg cell generation in neonates, which is partially mitigated with age. While the thymic Treg cell paucity caused by CNS4 deficiency did not result in autoimmunity on its own, it exacerbated autoimmune manifestations caused by disruption of the Aire gene. Thus, CNS4 enhancer activity ensures robust Treg cell differentiation early in postnatal life and, cooperatively with other tolerance mechanisms, minimizes autoimmunity.
2021-03-16 | GSE164117 | GEO
Project description:STAT5 transcription factor activation downstream of the Interleukin-2 receptor (IL-2R) induces expression of Foxp3, a critical step in the differentiation of regulatory T (Treg) cells. Due to the pleiotropic outputs of IL-2R signaling, it is unclear whether STAT5 acts directly on the Foxp3 locus to promote its expression . Here, we report that IL-2 – STAT5 signaling converged on an enhancer (CNS4) during Foxp3 induction. CNS4 facilitated and sustained the IL-2 dependent CD25+Foxp3– precursor to Treg cell transition in the thymus. Its deficiency resulted in markedly impaired Treg cell generation in neonates, which was partially mitigated with age. While the thymic Treg cell paucity caused by CNS4 deficiency did not result in autoimmunity on its own, it exacerbated autoimmune manifestations caused by disruption of the Aire gene. Thus, CNS4 enhancer activity ensures robust Treg cell differentiation early in postnatal life and cooperatively with other tolerance mechanisms, minimizes autoimmunity.
2021-03-17 | GSE169043 | GEO
Project description:STAT5 transcription factor activation downstream of the Interleukin-2 receptor (IL-2R) induces expression of Foxp3, a critical step in the differentiation of regulatory T (Treg) cells. Due to the pleiotropic outputs of IL-2R signaling, it is unclear whether STAT5 acts directly on the Foxp3 locus to promote its expression . Here, we report that IL-2 – STAT5 signaling converged on an enhancer (CNS4) during Foxp3 induction. CNS4 facilitated and sustained the IL-2 dependent CD25+Foxp3– precursor to Treg cell transition in the thymus. Its deficiency resulted in markedly impaired Treg cell generation in neonates, which was partially mitigated with age. While the thymic Treg cell paucity caused by CNS4 deficiency did not result in autoimmunity on its own, it exacerbated autoimmune manifestations caused by disruption of the Aire gene. Thus, CNS4 enhancer activity ensures robust Treg cell differentiation early in postnatal life and cooperatively with other tolerance mechanisms, minimizes autoimmunity.
2021-03-16 | GSE168829 | GEO
Project description:STAT5 activation downstream of the Interleukin-2 receptor (IL-2R) facilitates Foxp3 expression, which is required for the differentiation and function of regulatory T (Treg) cells. However, due to the pleiotropic roles of IL-2R signaling, it is unclear how STAT5 acts on the Foxp3 locus to promote Treg cell lineage commitment. Here, we report that IL-2–STAT5 signaling converges on an enhancer (CNS4) during early Foxp3 induction. CNS4 facilitates and sustains the IL-2–dependent CD25+Foxp3– precursor to Treg cell transition in the thymus. Its deficiency results in markedly impaired Treg cell generation in neonates, which is partially mitigated with age. While the thymic Treg cell paucity caused by CNS4 deficiency did not result in autoimmunity on its own, it exacerbated autoimmune manifestations caused by disruption of the Aire gene. Thus, CNS4 enhancer activity ensures robust Treg cell differentiation early in postnatal life and, cooperatively with other tolerance mechanisms, minimizes autoimmunity.
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Project description:The forkhead transcription factor Foxp3 is essential for the development of CD4+CD25+ regulatory T (Treg) cells and prevention of autoimmunity, but how it controls the Treg gene expression program is not understood. We describe here genome-wide location and expression data that identify Foxp3 target genes and report that many Foxp3 target genes are key modulators of T cell activation and function. Remarkably, the predominant effect of Foxp3 binding is to suppress the activation of target genes upon T cell stimulation. Foxp3 suppression of its targets appears to be crucial for the normal function of Treg cells because overactive variants of some target genes are known to be associated with autoimmune disease.
2007-01-27 | E-TABM-154 | biostudies-arrayexpress
Project description:Regulatory T (Treg) cells are involved in immune homeostasis and prevention of autoimmunity. Treg cells are characterized by the expression of the transcription factor FOXP3. Mutations in FOXP3 cause severe autoimmunity in mice and humans. However, the FOXP3-dependent molecular mechanisms leading to this severe phenotype are not well understood. Here we introduce a genome-wide transcription study of CD4+ T cells under different treatments in comparison to regulatory T cells. This study revealed a specific downregulation of SATB1 in Treg cells.
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