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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE26190 | GEO | 2011/12/14

SECONDARY ACCESSION(S): PRJNA135017

REPOSITORIES: GEO

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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

Gene expression analysis of ex-Foxp3 Th2 cells during Heligmosomoides polygyrus infection

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

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

miR-182 and miR-10a are Key Regulators of Treg specialisation and stability during Th2 and Th1-associated Inflammation

Project description:A variety of CD4+Foxp3+ Treg cell types have been described previously, indicating molecular heterogeneity within the Foxp3+ pool of CD4+ T cells. However, the factors that shape the transcriptomic identities of different Foxp3+ Treg cells are poorly understood. To identify the molecular pathways involved, we isolated CD4+Foxp3gfp+ cells from Th1-rich or Th2-rich environments following chronic Leishmania major or Schistosoma mansoni infection, respectively. Whole genome expression profiling and next generation small RNA sequencing revealed significantly different mRNA and miRNA profiles. In-silico analyses identified miR-10a and miR-182 as âregulatory miRNA hubsâ in CD4+Foxp3+ cells in Th1 and Th2-environments, respectively. Using in vitro and in vivo systems we identified that IL-12/IFNg down-regulated miR-10a and its putative transcription factor, Creb. Importantly, we demonstrated that miR-10a controls a suite of genes that regulate IFNg production in Th1-Treg cells. Also, Treg cells treated with IL-4 increased miR-182 and its putative transcription factor, cMaf. Up-regulation of miR-182 mitigated IL-2 secretion, in part through repression of IL2-promoting genes, including Bach2 and Cd2ap. This study indicates that CD4+Foxp3+ cells are influenced by their environment, and that Th1 or Th2 environments promote distinct miRNA pathways, preserving Treg stability and suppressor function. mouse infection vs. naÃ¯ve

2016-04-07 | E-GEOD-45976 | biostudies-arrayexpress

miR-182 and miR-10a are Key Regulators of Treg specialisation and stability during Th2 and Th1-associated Inflammation

Project description:A variety of CD4+Foxp3+ Treg cell types have been described previously, indicating molecular heterogeneity within the Foxp3+ pool of CD4+ T cells. However, the factors that shape the transcriptomic identities of different Foxp3+ Treg cells are poorly understood. To identify the molecular pathways involved, we isolated CD4+Foxp3gfp+ cells from Th1-rich or Th2-rich environments following chronic Leishmania major or Schistosoma mansoni infection, respectively. Whole genome expression profiling and next generation small RNA sequencing revealed significantly different mRNA and miRNA profiles. In-silico analyses identified miR-10a and miR-182 as ‘regulatory miRNA hubs’ in CD4+Foxp3+ cells in Th1 and Th2-environments, respectively. Using in vitro and in vivo systems we identified that IL-12/IFNg down-regulated miR-10a and its putative transcription factor, Creb. Importantly, we demonstrated that miR-10a controls a suite of genes that regulate IFNg production in Th1-Treg cells. Also, Treg cells treated with IL-4 increased miR-182 and its putative transcription factor, cMaf. Up-regulation of miR-182 mitigated IL-2 secretion, in part through repression of IL2-promoting genes, including Bach2 and Cd2ap. This study indicates that CD4+Foxp3+ cells are influenced by their environment, and that Th1 or Th2 environments promote distinct miRNA pathways, preserving Treg stability and suppressor function.

2016-04-07 | GSE45976 | GEO

A Foxp3 mutation drives Th2 effector function in regulatory T cells

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

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

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

FOXP3+ regulatory T cell development and function require histone/protein deacetylase 3

Project description:Treg dysfunction is associated with a variety of inflammatory diseases. Treg populations are defined by expression of the oligomeric transcription factor FOXP3 and inability to produce IL-2, a cytokine required for T cell maintenance and survival. FOXP3 activity is regulated post-translationally by histone/protein acetyltransferases and histone/protein deacetylases (HDACs). Here, we determined that HDAC3 mediates both the development and function of the two main Treg subsets, thymus-derived Tregs and induced Tregs (iTregs). We determined that HDAC3 and FOXP3 physically interact and that HDAC3 expression markedly reduces Il2 promoter activity. In murine models, conditional deletion of Hdac3 during thymic Treg development restored Treg production of IL-2 and blocked the suppressive function of Tregs. HDAC3-deficient mice died from autoimmunity by 4-6 weeks of age; however, injection of WT FOXP3+ Tregs prolonged survival. Adoptive transfer of Hdac3-deficient Tregs, unlike WT Tregs, did not control T cell proliferation in naive mice and did not prevent allograft rejection or colitis. HDAC3 also regulated the development of iTregs, as HDAC3-deficient conventional T cells were not converted into iTregs under polarizing conditions and produced large amounts of IL-2, IL-6, and IL-17. We conclude that HDAC3 is essential for the normal development and suppressive functions of thymic and peripheral FOXP3+ Tregs.

2015-05-19 | GSE68991 | GEO

Antigen specific human conventional T cells (CD154+) or regulatory T cells (CD137+) directed agains A. fumigatus or Birch pollen lysate isolated from Birch pollen allergic patients or healthy controls.

Project description:Foxp3+ regulatory T cells (Treg) play a central role for tolerance against self and innocuous environmental antigens. However, the role of antigen-specificity for Treg-mediated tolerance is only incompletely understood. Here we show by direct ex vivo characterization of human CD4+ T cells, that the response against innocuous airborne antigens, such as plant pollen or fungal spores, is dominated by memory-like antigen-specific Treg. Surprisingly, breakdown of tolerance in atopic donors was not accompanied by a quantitatively or qualitatively altered Treg response, but instead correlated with a striking dichotomy of Treg versus Th2 target specificity. Allergenic proteins, are selectively targeted by Th2 cells, but not Treg. Thus human Treg specific for airborne antigens maintain tolerance at mucosal sites and the failure to generate specific Treg against a subgroup of antigens provides a window of opportunity for allergy development.

2016-10-25 | GSE77018 | GEO

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