Comparison of expression profiles of Foxp3(+)epigenetics(-) T cells, Foxp3(-)epigenetics(+) T cells, and Foxp3(+)epigenetics(+) T cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE25252 | GEO | 2012/11/05
SECONDARY ACCESSION(S): PRJNA134675
REPOSITORIES: GEO
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Project description:Analysis of Foxp3(+)epigenetics(-) T cells, Foxp3(-)epigenetics(+) T cells, and Foxp3(+)epigenetics(+) T cells. Results indicate regulatory T cell (Treg) ontogenesis requires two independent processes, expression of the transcription factor Foxp3 and establishment of Treg epigenetic programs induced by T cell receptor (TCR) stimulation. GFP+CD4+ and GFP-CD4+ splenocytes were sorted from DEREG and DEREG/Scurfy mice. These cells were activated with anti-CD3/CD28 antibodies, and then transduced with Foxp3-expressing retrovirus (pGCSamIN, NGFR marker). NGFR+ T cells sorted were subjected to microarray analysis (Affymetrix, mouse genome 430 2.0 array). To normalize the experimental conditions, Tregs (GFP+ T cells from DEREG) and Tconv (GFP- T cells from DEREG) were also activated and transduced with empty vector. Two replicates each.
2012-11-05 | E-GEOD-25252 | biostudies-arrayexpress
Project description:The Foxp3 transcription factor is a crucial determinant of both regulatory T (TREG) cell development and their functional maintenance. Appropriate modulation of tolerogenic immune responses therefore requires tight regulation of Foxp3 transcriptional output, and this involves both transcriptional and post-translational regulation. Here, we show that during T cell activation, phosphorylation of Foxp3 in TREG cells can be regulated by a TGFβ Activated Kinase 1 (TAK1)-Nemo Like Kinase (NLK) signaling pathway. NLK interacts with Foxp3 in TREG cells and directly phosphorylates Foxp3 on multiple serine residues. This phosphorylation results in stabilization of Foxp3 protein levels by preventing association with the STUB1 E3-ubiquitin protein ligase, resulting in both reduced ubiquitination and proteasome-mediated degradation. Conditional TREG cell NLK-knockout (NLKTREG) results in decreased TREG cell-mediated immunosuppression in vivo and NLK-deficient TREG cell animals develop more severe experimental autoimmune encephalomyelitis. Our data suggest a molecular mechanism, in which stimulation of TCR-mediated signaling can induce a TAK1-NLK pathway to sustain Foxp3 transcriptional activity through stabilization of protein levels, thereby maintaining TREG cell suppressive function. Pharmacological manipulation of this phosphorylation-ubiquitination axis may provide therapeutic opportunities for regulating TREG cell function, for example during cancer immunotherapy.
2019-09-02 | PXD011164 | Pride
Project description:How do Treg cells control an autoimmune lesion? We depleted Foxp3+ Treg cells in autoimmune prone TCR transgenic BDC2.5 mice on the NOD background Kinetic of gene-expression changes in CD4 T cells isolated for pancreas and pancreas draining lymph node (PLN) of Foxp3-DTR.BDC2.5/NOD mice after Treg cell ablation Keywords: T cell activation/ differentiation after Treg depletion timecourse CD4 T cells were isolated from pancreas and PLN at 0, 15 and 24 hours after diphtheria toxin application into 4-6 week old female Foxp3-DTR.BDC2.5/NOD transgenic mice
2009-10-15 | E-GEOD-18136 | biostudies-arrayexpress
Project description:How do Treg cells control an autoimmune lesion? We depleted Foxp3+ Treg cells in autoimmune prone TCR transgenic BDC2.5 mice on the NOD background Kinetic of gene-expression changes in CD4 T cells isolated for pancreas and pancreas draining lymph node (PLN) of Foxp3-DTR.BDC2.5/NOD mice after Treg cell ablation Keywords: T cell activation/ differentiation after Treg depletion timecourse
2009-10-15 | GSE18136 | GEO
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
Project description:Regulatory T (Treg) cells, whose identity and function are defined by the transcription factor Foxp3, are indispensable for immune homeostasis. It is unclear whether Foxp3 exerts its Treg lineage specification function through active modification of the chromatin landscape and establishment of new enhancers or by exploiting a pre-existing enhancer landscape. Analysis of the chromatin accessibility of Foxp3-bound enhancers in Treg and Foxp3-negative T cells showed that Foxp3 was bound overwhelmingly to pre-accessible enhancers occupied by its cofactors in precursor cells or a structurally related predecessor. Furthermore, the bulk of Foxp3-bound Treg cell enhancers inaccessible in Foxp3- CD4+ cells became accessible upon T cell receptor activation prior to Foxp3 expression with only a small subset associated with several functionally important genes being exclusively Treg cell-specific. Thus, in a late cellular differentiation process Foxp3 defines Treg cell functionality in an “opportunistic” manner by largely exploiting the preformed enhancer network instead of establishing a new enhancer landscape. Array expression. Three cell types with 3-5 replicates each.
2012-09-28 | E-GEOD-40685 | biostudies-arrayexpress
Project description:The molecular programs involved in regulatory T (Treg) cell activation and homeostasis remain incompletely understood. Here we show that T cell receptor (TCR) signaling in Treg cells induces the nuclear translocation of Stk4, leading to the formation of a Stk4/NF-b p65/Foxp3 complex that regulates Foxp3 and p65-dependent transcriptional programs. The formation of this complex was stabilized by Stk4-dependent phosphorylation of Foxp3 serine 418. Stk4 deficiency in Treg cells, either alone or in synergy with that of its homologue Stk3, precipitated a fatal autoimmune lymphoproliferative disease characterized by decreased Treg cell p65 expression and nuclear translocation, impaired NF-b p65/Foxp3 complex formation and defective Treg cell activation. In an adoptive immunotherapy model, over-expression of p65 or the phosphomimetic Foxp3S418E in Stk3/4-deficient Treg cells ameliorated their immune regulatory defects. Our studies identify Stk3/4 as an essential TCR-responsive regulator of p65-Foxp3-dependent transcription that promotes Treg cell-mediated immune tolerance.
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Project description:Regulatory T cells (Treg) 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 meet 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. Foxp3 also imparts a selective advantage in ATP generation capacity, one that might be exploited as a source of adenosine for functional immunomodulation. In order to explore possible mechanisms for these differences in metabolism we conducted a 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 CD4+ T cells from various sources with Foxp3- activated CD4 T cells, as well as Treg from human peripheral blood. Gene set enrichment analysis of our proteomic datasets demonstrated that Foxp3 expression is associated with a significant up regulation of several members of the mitochondrial electron transport chain. Not only does Foxp3 influence genes directly concerned with immune function, but also with the energy generating functions of Treg.
2017-02-15 | PXD001906 | Pride
Project description:The transcription factor Helios is expressed in a large subset of Foxp3+ Tregs of both mouse and man. We previously demonstrated that Treg induced in peripheral sites (pTreg) from Foxp3- T conventional (Tconv) cells were Helios- and proposed that Helios is a marker of thymic derived Treg (tTreg). To compare the two Treg subpopulations, we generated Helios-GFP reporter mice and crossed them to Foxp3-RFP reporter mice. The Helios+ Treg population expressed a more activated phenotype and had a higher suppressive capacity in vitro. Both populations expressed a highly demethylated TSDR and both subsets were equivalent in their ability to suppress inflammatory bowel disease in vivo. However, Helios+ Treg more effectively inhibited the proliferation of activated, autoreactive splenocytes from scurfy mice. When Helios+ and Helios- Treg were transferred to lymphoreplete mice, both populations maintained comparable Foxp3 expression, but Foxp3 expression was less stable in Helios- Treg when transferred to lymphopenic mice. Gene expression profiling of the two populations demonstrated a large number of differentially expressed genes and that Helios- Treg subpopulation expressed certain genes normally expressed in CD4+Foxp3- T cells. TCR repertoire analysis indicated very little overlap between Helios+ and Helios- Treg. Thus, Helios+ and Helios- Treg subpopulations are phenotypically and functionally distinct, consistent with thymic and peripheral sites of origin, respectively. Because of their superior suppressive activity and enhanced stability Foxp3+Helios+ Treg represent the optimal Treg population for cellular immunotherapy.
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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