The transcription factor Foxp1 preserves integrity of an active Foxp3 locus in extrathymic Treg cells
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PROVIDER: PRJNA486174 | ENA |
REPOSITORIES: ENA
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Project description:In order to identify if there is any role of Foxp1 in the DNA demethylation of Foxp3 enhancer regions of induced Treg (iTreg) cells we performed bisulfite sequence analysis of Foxp1 deficient in vitro generated iTreg cells and compared their methylation status after 7 days of iTreg induction, at which point Foxp1 is deleted in the iTreg cells derived from Foxp3YFPCreFoxp1f/f (KO) mice.
2018-10-02 | GSE118595 | GEO
Project description: Not available
| S-EPMC6203760 | biostudies-literature
Project description:Regulatory T (Treg) cells, whose differentiation and function are controlled by transcription factor Foxp3, express high amounts of a closely related family member Foxp1, which is also expressed in quiescent naive T cells. Here we explored Foxp1 function in Treg cells. We found that a large number of Foxp3-bound genomic sites in Treg cells were occupied by Foxp1 in both Treg and conventional T cells. In Treg cells, Foxp1 markedly increased Foxp3 binding to these sites, which were enriched for canonic forkhead and Ets binding motifs. Foxp1 deficiency in Treg cells resulted in their impaired function and competitive fitness associated with markedly reduced CD25 expression and interleukin-2 (IL-2) responsiveness, diminished CTLA-4 and increased SATB1 expression. The characteristic patterns of CD25, Foxp3, and CTLA-4 expression in Treg cells were rescued, at least in part, upon strong IL-2 signaling. Our studies suggest that in addition to the Foxp1-mediated regulation of quiescence that is common to Treg and conventional T cells, Foxp1 has an essential non-redundant function in Treg cells by enforcing Foxp3-mediated regulation of gene expression and enabling efficient IL-2 signaling in these cells.
2019-01-18 | GSE121279 | GEO
Project description:Regulatory T (Treg) cells expressing the lineage-defining transcription factor Foxp3 are essential for the maintenance of immune tolerance. Foxp3 expression can be induced in a subset of developing self-reactive thymocytes to yield thymic Treg (tTreg) cells, critical for tolerance against self-antigens. Alternatively, activation of mature naïve T cells under non-inflammatory conditions can drive the differentiation of peripherally-induced Treg (pTreg) cells, thought to contribute to tolerance against commensal microbes and dietary antigens. While Foxp3 is indispensable for tTreg cell development and function, its role in pTreg cells has remained unknown. Here, we used a genetic fate mapping approach to characterize polyclonal pTreg cells induced by microbial colonization. We found that expression of a pTreg cell-specific gene expression program was initiated in the mesenteric lymph node (mLN) in a Foxp3-independent manner. Moreover, in contrast to Treg cells in secondary lymphoid tissues, colonic microbiota-dependent pTreg cells did not depend on Foxp3 for their fitness or lineage commitment and were capable of suppressing colonic effector T cell expansion in a Foxp3-independent manner. Rather, Foxp3 was required in a cell-intrinsic manner to limit IL-17 production and to prevent the expansion of intestinal mast cells. Our results suggest that, extrathymic Foxp3 induction likely acts as a mechanism to fine-tune the activity of Th17-like cells with Foxp3-independent regulatory functions.
2021-12-31 | GSE176236 | GEO
Project description:Regulatory T (Treg) cells expressing the lineage-defining transcription factor Foxp3 are essential for the maintenance of immune tolerance. Foxp3 expression can be induced in a subset of developing self-reactive thymocytes to yield thymic Treg (tTreg) cells, critical for tolerance against self-antigens. Alternatively, activation of mature naïve T cells under non-inflammatory conditions can drive the differentiation of peripherally-induced Treg (pTreg) cells, thought to contribute to tolerance against commensal microbes and dietary antigens. While Foxp3 is indispensable for tTreg cell development and function, its role in pTreg cells has remained unknown. Here, we used a genetic fate mapping approach to characterize polyclonal pTreg cells induced by microbial colonization. We found that expression of a pTreg cell-specific gene expression program was initiated in the mesenteric lymph node (mLN) in a Foxp3-independent manner. Moreover, in contrast to Treg cells in secondary lymphoid tissues, colonic microbiota-dependent pTreg cells did not depend on Foxp3 for their fitness or lineage commitment and were capable of suppressing colonic effector T cell expansion in a Foxp3-independent manner. Rather, Foxp3 was required in a cell-intrinsic manner to limit IL-17 production and to prevent the expansion of intestinal mast cells. Our results suggest that, extrathymic Foxp3 induction likely acts as a mechanism to fine-tune the activity of Th17-like cells with Foxp3-independent regulatory functions.
2021-12-31 | GSE176235 | GEO
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:Regulatory T (Treg) cells play central roles in maintaining immune homeostasis and self-tolerance. However, the molecular mechanisms underlying Treg cell homeostasis and suppressive function are still not fully understood. Here, we report that the deletion of another P subfamily members of the forkhead box (Foxp) subfamily member Foxp1 in Treg cells led to increased numbers of activated Treg (aTreg) cells at the expense of quiescent Treg cells, and also resulted in impaired Treg suppressive function. Mice with Foxp1-deficient Treg cells developed spontaneous inflammatory disease with age; they also had more severe inflammatory disease in colitis and experimental autoimmune encephalomyelitis (EAE) models. Mechanistically, we found that Foxp1 bound to the conserved noncoding sequence 2 (CNS2) element of the Foxp3 locus and helped maintain Treg suppressive function by stabilizing the Foxp3 expression. Furthermore, we found that Foxp1 and Foxp3 coordinated the regulation of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression levels. Taken together, our study demonstrates that Foxp1 plays critical roles in both maintaining Treg cell quiescence during homeostasis and regulating Treg suppressive function.
2019-04-10 | GSE121251 | 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:Here, we report on experiments in double-transgenic mice, in which RFP is expressed in all Foxp3+ Treg cells, whereas Foxp3-dependent GFP expression is exclusively confined to intrathymically induced Foxp3+ Treg cells. This novel molecular genetic tool enabled us to faithfully track and characterize naturally induced Treg cells of intrathymic (RFP+GFP+) and extrathymic (RFP+GFPM-bM-^HM-^R) origin in otherwise unmanipulated mice. These experiments directly demonstrate that extrathymically induced Treg cells substantially contribute to the overall pool of mature Foxp3+ Treg cells residing in peripheral lymphoid tissues of steady-state mice. Furthermore, we provide evidence that intra- and extrathymically induced Foxp3+ Treg cells represent distinct phenotypic and functional sublineages. CD4+CD25+ RFP+GFP- and CD4+CD25+ RFP+GFP+ T cells from pooled lymph nodes and pooled spleens of 20 mice were FACS sorted for RNA extraction and hybridization on Affymetrix microarrays in duplicates.
2014-07-09 | E-GEOD-59202 | biostudies-arrayexpress
Project description:The transcription factor Foxp3 is usually considered the master regulator for the CD4+CD25+ "Treg" lineage, which plays a key role in controlling immune and autoimmune responses, and is characterized by a unique transcriptional signature. We have performed a meta-analysis of this signature in Treg cells in several conditions to delineate the elements that can be ascribed to T cell activation, TGFbeta signaling, or Foxp3 itself. We find that these influences synergize to activate many of the signature’s components. Foxp3 and TGFbeta signaling have interconnected relationships, as Foxp3 is induced by TGFbeta while enhancing TGFbeta’s positive feedback loop. Much of the Treg signature cannot be ascribed to Foxp3, as it contains gene clusters that are co-regulated, but cannot be transactivated, by Foxp3. This suggests that the Treg lineage is specified at a higher level of regulation, upstream of Foxp3, which does control some of the lineage’s essential immunoregulatory attributes. Keywords: Cell population comparison
2007-12-04 | GSE7460 | GEO