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Genome-wide maps of H3K4me3 and H3K27me3 in human FOXP3+ Treg cells and the corresponding FOXP3-losing cells

ABSTRACT: Natural CD4+FOXP3+ regulatory T (Treg) cells constitute a unique T-cell lineage that plays a pivotal role in maintaining immune homeostasis and immune tolerance. Recent studies provide evidence for the heterogeneity and plasticity of the Treg cell lineage. However, the fate of human Treg cells after loss of FOXP3 expression and the underlying epigenetic mechanisms remain to be fully elucidated. Here, we compared gene expression profiles and histone methylation status on two histone H3 lysine residues (H3K4me3 and H3K27me3) of expanded FOXP3+ and corresponding FOXP3-losing Treg cells. DGE assay showed that human Treg cells down-regulated Treg signature genes, whereas up-regulated a set of Th lineages-associated genes, especially for Th2, such as GATA3, GFI1 and IL13, after in vitro expansion. Furthermore, we found that reprogramming of Treg cells was associated with histone modifications, as shown by decreased abundance of permissive H3K4me3 within down-regulated Treg signature genes, such as FOXP3, CTLA4 and LRRC32 loci, although with no significant changes in H3K27me3 modification. Thus, our results indicate that human Treg cells could convert into a Th-like cells upon in vitro expansion, displaying a gene expression signature dominated by Th2 lineage associated genes, and the histone methylation might contribute to such conversion.

ORGANISM(S): Homo sapiens

PROVIDER: GSE47510 | GEO | 2013/05/31

SECONDARY ACCESSION(S): PRJNA205935

REPOSITORIES: GEO

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Transcriptional profiling of FOXP3+ Treg cells and corresponding FOXP3-losing cells

Project description:Natural CD4+FOXP3+ regulatory T (Treg) cells constitute a unique T-cell lineage that plays a pivotal role in maintaining immune homeostasis and immune tolerance. Recent studies provide evidence for the heterogeneity and plasticity of the Treg cell lineage. However, the fate of human Treg cells after loss of FOXP3 expression and the underlying epigenetic mechanisms remain to be fully elucidated. Here, we compared gene expression profiles and histone methylation status on two histone H3 lysine residues (H3K4me3 and H3K27me3) of expanded FOXP3+ and corresponding FOXP3-losing Treg cells. DGE assay showed that human Treg cells down-regulated Treg signature genes, whereas up-regulated a set of Th lineages-associated genes, especially for Th2, such as GATA3, GFI1 and IL13, after in vitro expansion. Furthermore, we found that reprogramming of Treg cells was associated with histone modifications, as shown by decreased abundance of permissive H3K4me3 within down-regulated Treg signature genes, such as FOXP3, CTLA4 and LRRC32 loci, although with no significant changes in H3K27me3 modification. Thus, our results indicate that human Treg cells could convert into a Th-like cells upon in vitro expansion, displaying a gene expression signature dominated by Th2 lineage associated genes, and the histone methylation might contribute to such conversion. mRNA profiles of in-vitro-expanded FOXP3+ Treg and FOXP3-losing Treg cells generated by deep sequencing.

2013-06-06 | E-GEOD-47636 | biostudies-arrayexpress

Genome-wide maps of H3K4me3 and H3K27me3 in human FOXP3+ Treg cells and the corresponding FOXP3-losing cells

Project description:Natural CD4+FOXP3+ regulatory T (Treg) cells constitute a unique T-cell lineage that plays a pivotal role in maintaining immune homeostasis and immune tolerance. Recent studies provide evidence for the heterogeneity and plasticity of the Treg cell lineage. However, the fate of human Treg cells after loss of FOXP3 expression and the underlying epigenetic mechanisms remain to be fully elucidated. Here, we compared gene expression profiles and histone methylation status on two histone H3 lysine residues (H3K4me3 and H3K27me3) of expanded FOXP3+ and corresponding FOXP3-losing Treg cells. DGE assay showed that human Treg cells down-regulated Treg signature genes, whereas up-regulated a set of Th lineages-associated genes, especially for Th2, such as GATA3, GFI1 and IL13, after in vitro expansion. Furthermore, we found that reprogramming of Treg cells was associated with histone modifications, as shown by decreased abundance of permissive H3K4me3 within down-regulated Treg signature genes, such as FOXP3, CTLA4 and LRRC32 loci, although with no significant changes in H3K27me3 modification. Thus, our results indicate that human Treg cells could convert into a Th-like cells upon in vitro expansion, displaying a gene expression signature dominated by Th2 lineage associated genes, and the histone methylation might contribute to such conversion. Genome-wide analysis of histone H3 K4 and K27 trimethylation in expanded human FOXP3+ Treg cells and FOXP3-losing Treg cells

2013-05-31 | E-GEOD-47510 | biostudies-arrayexpress

Transcriptional profiling of FOXP3+ Treg cells and corresponding FOXP3-losing cells

2013-06-06 | GSE47636 | GEO

Dominant Th2 differentiation of human regulatory T cells upon loss of FOXP3 expression

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

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2017-05-04 | GSE98518 | GEO

Dominant Th2 differentiation of human regulatory T cells upon loss of FOXP3 expression

2011-12-14 | GSE26190 | GEO

Ndfip1 restricts mTORC1 signalling and glycolysis in regulatory T cells to prevent autoinflammatory disease

Project description:Project abstract: Foxp3+ T regulatory (Treg) cells have important functions in suppressing immune cell activation and establishing normal immune homeostasis. How Treg cells maintain their identity is not completely understood. Here we show that Ndfip1, a co-activator of Nedd4-family E3 ubiquitin ligases, is required for Treg cell stability and function. Ndfip1 deletion in Treg cells disrupts immune homeostasis and results in autoinflammatory disease. Ndfip1-deficient Treg cells are highly proliferative and are more likely to lose Foxp3 expression to become IL-4-producing TH2 effector cells. Proteomic analyses indicate that Ndfip1 deficiency alters the metabolic signature of Treg cells. Metabolic profiling reveals elevated glycolysis and increased mTORC1 signalling. Additional data suggest that Ndfip1 restricts Treg cell metabolic capacity and IL-4 production via distinct mechanisms. Thus, Ndfip1 preserves Treg lineage stability by preventing the expansion of highly proliferative and metabolically active cells that can cause immunopathology via secretion of IL-4.

2017-04-19 | PXD006251 | Pride

Human activated Treg cells and retrovirally engineered Th cells, transduced with GARP, FOXP3 or control GFP vector

Project description:Goals and objectives of this study: to identify genes of the Treg signature induced by consitutive expression of GARP or FOXP3 in antigen-specific Th cells with potential role for stabililization & maintenance of the regulatory program. Keywords: T-cell receptor stimulation, gene-regulation, comparative gene expression profiling, cell type comparison, human, regulatory T cells, FOXP3, GARP Human alloantigen-specific Treg cells (THU) and Th cells (CD4-39), established and described recently (Ocklenburg et al.. Lab Invest.2006; 86: 724-737), were sitmulated for 3 days with cognate antigen (EBV B cells) and IL2 as described (Ocklenburg et al.. Lab Invest.2006; 86: 724-737) and analyzed using human Affymetrix U133 2.0 in monoplicate. Th cells had been transduced with a retroviral vector containing human GARP (LRRC32) or FOXP3 and an IRES-driven GFP as marker or empty GFP control, sorted for GFP+, expanded as described recently (Ocklenburg et al.. Lab Invest.2006; 86: 724-737), and characterized functially, phenotypically, and genetically as described (WO/2007/113301). Abbreviations: Treg THU d3 = alloantigen-specific Treg cells; GFP d3 = GFP-transduced alloantigen-specific Th cells (CD4-39); FoxP3 d3 = FOXP-transduced alloantigen-specific Th cells (CD4-39); Garp d3 = GARP-transduced alloantigen-specific Th cells (CD4-39); all stimulated for 3 days (=d3) with EBV B cells and IL2.

2009-04-20 | E-GEOD-13234 | biostudies-arrayexpress

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2018-12-31 | GSE112176 | GEO

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