A Foxp3 mutation drives Th2 effector function in regulatory T cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA443915 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6876290_1.fastq.gz | Fastqsanger.gz | |||
| SRR6876290_2.fastq.gz | Fastqsanger.gz | |||
| SRR6876291_1.fastq.gz | Fastqsanger.gz | |||
| SRR6876291_2.fastq.gz | Fastqsanger.gz | |||
| SRR6876282.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 16 |
Similar Datasets
Project description:Regulatory T (Treg) cells maintain immune tolerance through the action of the master regulator FOXP3, a transcription factor crucial for Treg cells function and homeostasis. We identified an IPEX patient with a FOXP3 mutation in the domain swap interface of the protein (mutant M370I). Recapitulation of this Foxp3 variant in mice led to an autoimmune syndrome similar to the patient and consistent with an unrestrained Th2 immune response. Genomic analysis of Treg cells by RNA-seq, Foxp3 ChIP-seq and H3K27ac-HiChIP revealed a specific de-repression of the T helper type 2 (Th2) transcriptional program leading to the generation of Th2-like Treg cells that are unable to suppress extrinsic Th2 cells. Th2-like Treg cells are characterized by increased intra-chromosomal interactions in the Th2 locus leading to type-2 cytokines production. Our research provides cellular and molecular characterizations of mechanisms used by Foxp3 to restrain Th2 transdifferentiation and promote optimal Treg suppressive function and stability.
2018-12-31 | GSE112176 | GEO
Project description:Gene expression of Treg cells that have lost Foxp3 expression and acquired Il4 expression following adoptive transfer into T-cell deficient mice (HpTR-IL-4gfp+), cmpared to conventional Treg cells isolated from H. polygyrus-infected wild-type mice (HpTR) and Th2 cells generated from naïve T cells following adoptive transfer into H. polygyrus-infected T-cell deficient mice (nT-IL-4gfp+). Immunity to intestinal helminth infections requires the rapid activation of T helper 2 (Th2) cells. However, simultaneous expansion of regulatory CD4+Foxp3+ T (Treg) cells impedes protective responses, resulting in chronic infections. The ratio between regulatory and effector T cells can therefore determine the outcome of infection. The re-differentiation of Treg into T helper (Th) cells has been identified in hyper-inflammatory diseases. In this study, we asked whether ex-Treg Th2 cells develop and contribute to type 2 immunity. Using multi-gene reporter and fate-reporter systems we demonstrate that a significant proportion of Th2 cells derive from Foxp3+ cells following Heligmosomoides polygyrus infection and airway allergy. Ex-Foxp3 Th2 cells exhibit characteristic Th2 effector functions and provide immunity to H. polygyrus. Through selective deletion of Il4ra on Foxp3+ cells, we further demonstrate IL-4 is required for the development of ex-Foxp3 Th2 cells. Collectively, our findings indicate that converting Treg cells into Th2 cells could concomitantly enhance Th2 cells and limit Treg-mediated suppression.
2017-05-04 | GSE98518 | GEO
Project description:CD4+CD25+FOXP3+ regulatory T cells (Treg) are pivotal for peripheral self-tolerance. They prevent immune responses to auto- and alloantigens and are thus under close scrutiny as cellular therapeutics for autoimmune diseases and the prevention or treatment of alloresponses after organ or stem cell transplantation. We previously showed that human Treg cells with a memory cell phenotype, but not those with a naïve phenotype, rapidly down-regulate expression of the lineage-defining transcription factor forkhead box P3 (FOXP3) upon in vitro expansion. We now compared the transcriptomes of stable FOXP3+ Treg and converted FOXP3- 'ex-Treg' cells by applying a newly developed intranuclear staining protocol that permits the isolation of intact mRNA from fixed, permeabilized and FACS-purified cell populations. Whole genome microarray analysis revealed strong and selective upregulation of Th2 signature genes, including GATA-3, IL-4, IL-5 and IL-13, upon downregulation of FOXP3. Th2 differentiation of converted, FOXP3- ex-Treg cells occurred even under non-polarizing conditions and could not be prevented by IL-4 signaling blockade. Thus, our studies identify Th2 differentiation as the default developmental program of human Treg cells after downregulation of FOXP3. RNA preparations from FOXP3 stained in vitro expanded CD4+CD25highCD45RA- “memory” Treg cells from five independent donors were analyzed using Whole Human Genome Oligo Microarrays (Agilent). An adapted FOXP3 staining procedure to stain FOXP3 in human regulatory T cells to isolate intact RNA for microarray hybridization was developed (see extract protocol).
2011-12-14 | E-GEOD-26190 | biostudies-arrayexpress
Project description:CD4+CD25+FOXP3+ regulatory T cells (Treg) are pivotal for peripheral self-tolerance. They prevent immune responses to auto- and alloantigens and are thus under close scrutiny as cellular therapeutics for autoimmune diseases and the prevention or treatment of alloresponses after organ or stem cell transplantation. We previously showed that human Treg cells with a memory cell phenotype, but not those with a naïve phenotype, rapidly down-regulate expression of the lineage-defining transcription factor forkhead box P3 (FOXP3) upon in vitro expansion. We now compared the transcriptomes of stable FOXP3+ Treg and converted FOXP3- 'ex-Treg' cells by applying a newly developed intranuclear staining protocol that permits the isolation of intact mRNA from fixed, permeabilized and FACS-purified cell populations. Whole genome microarray analysis revealed strong and selective upregulation of Th2 signature genes, including GATA-3, IL-4, IL-5 and IL-13, upon downregulation of FOXP3. Th2 differentiation of converted, FOXP3- ex-Treg cells occurred even under non-polarizing conditions and could not be prevented by IL-4 signaling blockade. Thus, our studies identify Th2 differentiation as the default developmental program of human Treg cells after downregulation of FOXP3.
2011-12-14 | GSE26190 | GEO
Project description:Studies of the monogenic autoimmune disease immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) have elucidated the essential function of the transcription factor FOXP3 and thymic-derived regulatory T cells (Tregs) in controlling peripheral tolerance. However, the presence and the source of autoreactive T cells in IPEX remain undetermined. Here, we investigated how FOXP3 deficiency affects the T cell receptor (TCR) repertoire and Treg stability in vivo and compared T cell abnormalities in patients with IPEX to those in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED). To study Tregs independently of their phenotype and to analyze T cell autoreactivity, we combined Treg-specific demethylation region analyses, single-cell multi-omic profiling, and bulk TCR sequencing. We found that patients with IPEX, unlike patients with APECED, have expanded autoreactive T cells originating from both autoreactive effector T cells (Teffs) and Tregs. In addition, a fraction of the expanded Tregs lost their phenotypic and functional markers including CD25 and often also FOXP3. Functional experiments with CRISPR/Cas9-mediated FOXP3 knock-out Treg and Tregs from patients with IPEX indicated that the patients’ Tregs gain a Th2 skewed Teff-like function, which is consistent with immune dysregulation observed in these patients. Analyses of FOXP3 mutation-carrier mothers and a patient with IPEX after hematopoietic stem cell transplantation, indicated that Tregs expressing non-mutated FOXP3 prevent the accumulation of autoreactive Teffs and unstable Tregs. Collectively, we describe Treg instability and Teff autoreactivity in patients with IPEX. These findings could be directly used for diagnostic and prognostic purposes and for monitoring the effects of immunomodulatory treatments.
2023-12-20 | GSE247274 | GEO
Project description:Regulatory T cells have been shown to adopt a catabolic metabolic programme with increased capacity for fatty acid oxidation fuelled oxidative phosphorylation (OXPHOS). The role of Foxp3 in this metabolic shift is poorly understood. Here we show that Foxp3 was sufficient to induce a significant increase in the spare respiratory capacity of the cell, the extra OXPHOS capacity available to a cell to increased demands on energy in response to work. Foxp3-expressing cells were enhanced in their ability to utilise palmitate for respiration and in addition the activity of electron transport complexes I, II and IV were enhanced following Foxp3 expression. ATP was secreted by both T effector and regulatory T cells and was reduced by mitochondrial respiration inhibitors. Thus Foxp3 imparts a selective advantage in ATP generation capacity to the cell and may exploit this as a source of adenosine for functional immunomodulation. In order to explore possible mechanisms for these differences in metabolism we conducted a comparative quantitative proteomics study to compare the contribution of TGFβ and the transcription factor Foxp3 to the Treg proteome. We used quantitative mass spectrometry to examine differences between proteomes of nuclear and cytoplasmic Foxp3-containing T cells and Foxp3 positive iTreg and Foxp3 negative activated CD4 T cells in addition to human peripheral blood natural Treg. Gene set enrichment analysis of our proteomic datasets demonstrated that Foxp3 drives a significant up regulation of several members of the mitochondrial electron transport chain.
2017-02-15 | PXD001789 | Pride
Project description:Naïve CD4+ T cells were isolated from spleen of AND TcR transgenic/green fluorescence protein (GFP) transgenic mice (Kaye et al., Nature 1989;341:746, Wright et al, Blood 2001;97:2278) that recognize a peptide of pigeon cytochrome C in the context of I-Ek and express CD44lo, CD62Lhi, CD45RBhi, and CD25-. After 4 days in vitro stimulation with antigen presenting cells (APC) under either Th1 or Th2 condition, naïve cells become Th1 or Th2 effector cells expressing CD44hi, CD62L lo, CD45RBhi, and CD25+. Additional 3 days culture in the absence of APC, those effector cells become rested expressing a phenotype similar to memory cells (CD44 hi, CD62L lo, CD45RB lo and CD25-). These rested effector cells were adaptively transferred into thymectomized, lethally irradiated, and T cell depleted bone marrow reconstituted mice and memory cells were isolated after 4-12 weeks by flow sort. Generation and purification of Th1 and Th2 effector and memory CD4+ T cells of 42 samples.
2010-06-10 | E-GEOD-8352 | biostudies-arrayexpress
Project description:Gene expression profiles were compared between regulatory T cells (Treg) and Effector CD4+ T cells in healthy B6 mice and sick mice with scurfy mutation. We used microarrays to elucidate the molecular mechanisms underlying the suppression function of the Treg cells. Experiment Overall Design: To identify candidate genes that might be related to the suppressive activity, the Treg cells expressing functional and mutant Foxp3 transcription factor were compared
2009-09-04 | E-GEOD-11775 | 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. 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:Naïve CD4+ T cells were isolated from spleen of AND TcR transgenic/green fluorescence protein (GFP) transgenic mice (Kaye et al., Nature 1989;341:746, Wright et al, Blood 2001;97:2278) that recognize a peptide of pigeon cytochrome C in the context of I-Ek and express CD44lo, CD62Lhi, CD45RBhi, and CD25-. After 4 days in vitro stimulation with antigen presenting cells (APC) under either Th1 or Th2 condition, naïve cells become Th1 or Th2 effector cells expressing CD44hi, CD62L lo, CD45RBhi, and CD25+. Additional 3 days culture in the absence of APC, those effector cells become rested expressing a phenotype similar to memory cells (CD44 hi, CD62L lo, CD45RB lo and CD25-). These rested effector cells were adaptively transferred into thymectomized, lethally irradiated, and T cell depleted bone marrow reconstituted mice and memory cells were isolated after 4-12 weeks by flow sort. Keywords: Microarray analysis of Th1 and Th2 effector and memory CD4+ T cells
2007-07-07 | GSE8352 | GEO