Different molecular complexes that mediate transcriptional induction and repression by FoxP3
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE102281 | GEO | 2017/08/07
SECONDARY ACCESSION(S): PRJNA397333
REPOSITORIES: GEO
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Project description:FoxP3 conditions the transcriptional signature and functional facets of regulatory T cells (Treg cells). Its mechanism of action, whether as an activator or a repressor, has remained unclear. Here, chromatin analysis showed that FoxP3 bound active enhancer elements, not repressed chromatin, around loci over- or under-expressed in Treg cells. We evaluated the impact of a panel of FoxP3 mutants on its transcriptional activity and interactions with DNA, transcriptional cofactors and chromatin. Computational integration, confirmed by biochemical interaction and size analyses, showed that FoxP3 existed in distinct multimolecular complexes. It was active and primarily an activator when complexed with the transcriptional factors RELA, IKZF2 and KAT5. In contrast, FoxP3 was inactive when complexed with the histone methyltransferase EZH2 and transcription factors YY1 and IKZF3. The latter complex partitioned to a peripheral region of the nucleus, as shown by super-resolution microscopy. Thus, FoxP3 acts in multimodal fashion to directly activate or repress transcription, in a context- and partner-dependent manner, to govern Treg cell phenotypes.
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Project description:We previously found that NF-kB inducing kinase (NIK) overexpression in T cells via CD4 promoter driven transgene induction caused lethal autoimmunity in mice. Autoimmunity was associated with increased conventional T cell effector function and decreased regulatory T cell (Foxp3+CD4+) suppression. The goal in this study was to elucidate global transcriptional changes in Foxp3+CD4+ and Foxp3-CD4+ T cells intrinsically caused by chronic NIK overexpression in these cell types. Total RNA from FACS-sorted NIKtg and WT Foxp3RFP+CD4+ and Foxp3RFP-CD4+ harvested from NIKtg/CD4Cre/Foxp3RFP + WT/Thy1.1/Foxp3RFP mixed bone marrow chimeric mice, >8 weeks after bone marrow reconstitution.
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Project description:CD4+Foxp3+ regulatory T cells (Treg) are essential for immune homeostasis and maintenance of self-tolerance. They are produced in the thymus and also generated de novo in the periphery in a TGFB dependent manner. Foxp3+ Treg are also required to achieve tolerance to transplanted tissues when induced by co-receptor or costimulation blockade. Using TCR transgenic mice to avoid issues of autoimmune pathology we show that Foxp3 expression is necessary and sufficient for tissue tolerance by coreceptor blockade. Moreover, the known need in tolerance induction for TGFB signalling to T cells, can wholly be explained by its role in induction of Foxp3, as such signalling proved dispensable for the suppressive process. We analysed the relative contribution of TGFB and Foxp3 on the transcriptome of TGFB induced Treg. TGFB elicited a large set of downregulated signature genes. The number of genes uniquely modulated due to the influence of Foxp3 alone was surprisingly limited. Retroviral conditional Foxp3 expression proved sufficient to confer transplant-suppressive potency on CD4+ T cells, and was lost once nuclear Foxp3 expression was extinguished. Thus despite the large genetic influence of TGFB exposure on iTreg the crucial Foxp3 influenced signature independent of TGFB is small. These data support a dual role for TGFB and Foxp3 in induced tolerance, where TGFB stimulates Foxp3 expression whose sustained expression is associated with acquisition of tolerance 21 samples were analyzed. 5 replicates of Marilyn.Foxp3hCD2 activated (HY)(Untreated) and TGFB-induced (HYT) cells sorted as CD4+hCD2+ and CD4+hCD2- and 3 replicates of Marilyn.Foxp3-/- activated and TGFβ-experienced (but Foxp3-) cells sorted as CD4+CD2. Pairwise comparisons were generated for the Marilyn Foxp3hCD2 UT versus TGFB induced populations and also for the Marilyn Foxp3-/- UT versus the TGFB experienced cells sorted as CD4+CD2
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Project description:The forkhead DNA-binding protein FOXP3 is critical for the development and suppressive function of CD4+CD25+ regulatory T cells (TREG), which play a key role in maintaining self tolerance. Functionally, FOXP3 is capable of repressing transcription of cytokine genes regulated by the Nuclear Factor of Activated T cells (NFAT). Various mechanisms have been proposed by which FOXP3 mediates these effects. Using novel HEK cell lines that inducibly express either wild-type (WT) or mutant FOXP3, we have identified genome-wide expression patterns showing among other features that NFAT2 as an early target of FOXP3-mediated transcriptional repression. Six biological replicates of wild-type induced FOXP3 cell lines and six biological replicates of mutated FOXP3 cell line were studied.
2010-05-15 | E-GEOD-13798 | biostudies-arrayexpress
Project description:Single-cell RNAseq (10x Genomics) analysis of mouse splenic CD4+ T cells in WT and ∆Foxp3 mice and in WT/∆Foxp3 bone marrow chimeras. Mouse CD4+T cells in 21-day-old male WT and ∆Foxp3 mice were isolated from spleen by flow cytometry as DAPI–TCRβ+CD4+ cells for 10x Genomics Single Cell 3′ Reagent Kit (V2 chemistry, one sample per channel). For bone marrow chimera experiment: 7 week-old CD45.2-recipient mice were irradiated with 1000 Rad, reconstituted with 4 million CD3-depleted bone marrow cells: 50% CD45.1 x Foxp3-IRES-GFP (WT, 21d-old male) and 50% Foxp3DeltaEGFPiCre/RFP x ROSA-YFP x CD45.1/2 (scurfy, 21d-old male). 10 weeks later, spleen were harvested and tagged using a different Hashtags fo each mouse. ∆Foxp3 CD4+ T cells were sorted as DAPI–TCRb+CD4+CD45.1+CD45.2+. WT CD4+ T cells were sorted as DAPI–TCRb+CD4+CD45.1+CD45.2–. Control WT DAPI–TCRb+CD4+GFP+ Treg cells and GFP- Tconvs cells were also tagged and sorted. Samples with different hastags were pooled before single cell encapsulation using 10x Genomics Single Cell 3′ Reagent Kit (V3 chemistry).
2021-02-26 | GSE167575 | GEO
Project description:The forkhead DNA-binding protein FOXP3 is critical for the development and suppressive function of CD4+CD25+ regulatory T cells (TREG), which play a key role in maintaining self tolerance. Functionally, FOXP3 is capable of repressing transcription of cytokine genes regulated by the Nuclear Factor of Activated T cells (NFAT). Various mechanisms have been proposed by which FOXP3 mediates these effects. Using novel HEK cell lines that inducibly express either wild-type (WT) or mutant FOXP3, we have identified genome-wide expression patterns showing among other features that NFAT2 as an early target of FOXP3-mediated transcriptional repression.
2008-12-04 | GSE13798 | GEO
Project description:The CD4+Foxp3+ regulatory T cells play an essential role in maintaining tolerance via their suppressive function on conventional T cells. The intracellular signaling pathways that regulate Foxp3 expression are largely unknown. In this study we describe a novel inhibitory role for AKT in regulating de novo induction of Foxp3 both in vivo and in vitro. A constitutively active allele of AKT significantly diminished TGF-â induced Foxp3 induction via a rapamycin-sensitive pathway, establishing a role for the AKT-mTOR axis in Treg cells. Moreover, the observed impairment in Foxp3 induction was paralleled by a selective downmodulation of the imparted Treg transcriptional signature highlighting the importance of the balance of intracellular signals in Treg differentiation . Our results provide a basis for further elucidation of molecular mechanisms that regulate Foxp3 induction and identify AKT as an important negative regulator of this process. Keywords: Cell population comparison
2008-02-15 | GSE7596 | GEO
Project description:CD4+Foxp3+ regulatory T cells (Treg) are essential for immune homeostasis and maintenance of self-tolerance. They are produced in the thymus and also generated de novo in the periphery in a TGFB dependent manner. Foxp3+ Treg are also required to achieve tolerance to transplanted tissues when induced by co-receptor or costimulation blockade. Using TCR transgenic mice to avoid issues of autoimmune pathology we show that Foxp3 expression is necessary and sufficient for tissue tolerance by coreceptor blockade. Moreover, the known need in tolerance induction for TGFB signalling to T cells, can wholly be explained by its role in induction of Foxp3, as such signalling proved dispensable for the suppressive process. We analysed the relative contribution of TGFB and Foxp3 on the transcriptome of TGFB induced Treg. TGFB elicited a large set of downregulated signature genes. The number of genes uniquely modulated due to the influence of Foxp3 alone was surprisingly limited. Retroviral conditional Foxp3 expression proved sufficient to confer transplant-suppressive potency on CD4+ T cells, and was lost once nuclear Foxp3 expression was extinguished. Thus despite the large genetic influence of TGFB exposure on iTreg the crucial Foxp3 influenced signature independent of TGFB is small. These data support a dual role for TGFB and Foxp3 in induced tolerance, where TGFB stimulates Foxp3 expression whose sustained expression is associated with acquisition of tolerance
2012-10-03 | GSE39529 | 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.
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Project description:We performed RNA-seq analysis of Tregs isolated from Foxp3RFP/∆2Foxp3∆CNS1-cre-Thy1.1Rosa26LSL-YFP female mice. CD4+YFP+RFP+ (WT Tregs) and CD4+YFP+RFP- (Foxp3∆2 Tregs) cells were sorted from lymph nodes and spleen to a typical purity of >95% We detected 638 differentially expressed genes (DEGs, FDR < 0.05) between Foxp3∆2 and WT Tregs
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