The splicing isoform Foxp3∆2 differentially regulates tTregs and pTregs homeostasis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA990694 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25114328_1.fastq.gz | Fastqsanger.gz | |||
| SRR25114328_2.fastq.gz | Fastqsanger.gz | |||
| SRR25114329_1.fastq.gz | Fastqsanger.gz | |||
| SRR25114329_2.fastq.gz | Fastqsanger.gz | |||
| SRR25114330_1.fastq.gz | Fastqsanger.gz |
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Project description:Foxp3 is the master transcription factor for the regulatory T cells (Tregs). Alternative splicing of human Foxp3 results in the expression of two isoforms: the full-length and an exon 2-deleted protein. Here, AlphaFold2 predictions and in vitro experiments demonstrate that the N-terminal domain of Foxp3 inhibits DNA binding by moving toward the C-terminus and that this movement is mediated by exon 2. Consequently, we find Foxp3∆2-bearing tTregs in the peripheral lymphoid organ are less sensitive to TCR due to the enhanced binding of Foxp3∆2 to the Batf promoter and are unsusceptible to IL-2. In contrast, among RORγt+ pTregs in the large intestine, Foxp3∆2 pTregs express much more RORγt-related genes conferring a competitive advantage. Together, our results reveal that alternative splicing of exon 2 generates a constitutively active form of Foxp3, which plays a differential role in regulating tTregs and pTregs homeostasis.
2023-11-19 | GSE236356 | GEO
Project description:Differing from the mouse Foxp3 gene that encodes only one protein product, human FOXP3 encodes two major isoforms through alternative splicing – a longer isoform (FOXP3 FL) containing all the coding exons and the other shorter isoform lacking the amino acids encoded by exon 2 (FOXP3 ΔE2). The two isoforms are naturally expressed in humans yet their differences in controlling regulatory T cell phenotype and functionality remains unclear. Here we show that patients expressing only the shorter isoform failed to maintain self-tolerance and developed IPEX syndrome. Mice with Foxp3 exon 2 deletion developed excessive TFH and GC B cell responses and systemic autoimmune disease with anti-dsDNA and anti-nuclear autoantibody production and immune-complex glomerulonephritis. Regulatory T cells expressing FOXP3 ΔE2 were unstable and sufficient to induce autoimmunity when transferred into Tcrb-deficient mice. Mechanistically, FOXP3 ΔE2 isoform allows increased expression of selected cytokines but decreased expression of a set of Foxp3 positive regulators without altered binding to these gene loci. We demonstrate that exon 2 of FOXP3 is required to maintain Treg stability and immune homeostasis.
2022-06-27 | GSE199477 | GEO
Project description:Differing from the mouse Foxp3 gene that encodes only one protein product, human FOXP3 encodes two major isoforms through alternative splicing – a longer isoform (FOXP3 FL) containing all the coding exons and the other shorter isoform lacking the amino acids encoded by exon 2 (FOXP3 ΔE2). The two isoforms are naturally expressed in humans yet their differences in controlling regulatory T cell phenotype and functionality remains unclear. Here we show that patients expressing only the shorter isoform failed to maintain self-tolerance and developed IPEX syndrome. Mice with Foxp3 exon 2 deletion developed excessive TFH and GC B cell responses and systemic autoimmune disease with anti-dsDNA and anti-nuclear autoantibody production and immune-complex glomerulonephritis. Regulatory T cells expressing FOXP3 ΔE2 were unstable and sufficient to induce autoimmunity when transferred into Tcrb-deficient mice. Mechanistically, FOXP3 ΔE2 isoform allows increased expression of selected cytokines but decreased expression of a set of Foxp3 positive regulators without altered binding to these gene loci. We demonstrate that exon 2 of FOXP3 is required to maintain Treg stability and immune homeostasis.
2022-06-27 | GSE199277 | GEO
Project description:RNA alternative splicing (AS) expands the regulatory potential of eukaryotic genomes. The mechanisms regulating liver-specific AS profiles and their contribution to liver function are poorly understood. Here, we identify a key role for the splicing factor RNA-binding Fox protein-2 (RBFOX2) in maintaining cholesterol homeostasis in an obesogenic environment in the liver. Using enhanced individual-nucleotide resolution UV-crosslinking and immunoprecipitation (eiCLIP), we identify physiologically relevant targets of RBFOX2 in mouse liver, including the scavenger receptor class B type I (Scarb1). RBFOX2 function is decreased in the liver in diet-induced obesity, causing a Scarb1 isoform switch and alteration of hepatocyte lipid homeostasis. Our findings demonstrate that specific AS programmes actively maintain liver physiology, and underlie the lipotoxic effects of obesogenic diets when dysregulated. Splice-switching oligonucleotides targeting this network alleviate obesityinduced inflammation in the liver and promote an anti-atherogenic lipoprotein profile in the blood, underscoring the potential of isoform-specific RNA therapeutics for treating metabolism-associated diseases.
2022-11-28 | PXD036976 | Pride
Project description:Autoimmune disease is caused by environmental and genetic factors. Genetic factors associated with increased susceptibility to multiple sclerosis (MS), an autoimmune disease of the central nervous system, have been identified, but their mechanisms of action are incompletely understood.(Briggs, 2019) We previously established that the association between MS risk and the interleukin-7 receptor-a gene (IL7R) is mediated by alternative splicing of IL7R transcripts.(Gregory et al., 2007) This splicing is regulated by the RNA helicase DEAD Box Polypeptide 39B (DDX39B), which shows genetic and functional epistasis with IL7R in enhancing MS risk (Galarza-Munoz et al., 2017). Here we discover that DDX39B, which is also known by immunologists as BAT1 (Spies et al., 1989), impacts the expression of many genes likely to play roles in autoimmunity.(Allcock et al., 2001; Degli-Esposti et al., 1992) We show that DDX39B controls expression of Forkhead Box P3 (FOXP3), a master regulator of the development, maintenance and function of CD4+/CD25+ T regulatory cells(Georgiev et al., 2019; Josefowicz et al., 2012) and repressor of autoimmunity (Bennett et al., 2001; Brunkow et al., 2001; Chatila et al., 2000; Wildin et al., 2001). Splicing of FOXP3 introns, which belong to a new subclass of introns with C-rich polypyrimidine tracts, was exquisitely sensitive to DDX39B levels, making FOXP3 expression highly sensitive to the levels of this RNA helicase. Low DDX39B levels in primary human T regulatory cells lead to loss of regulatory gene expression and cytokine signatures and gain of effector ones. Given the importance of FOXP3 in autoimmunity, this work cements DDX39B as a critically important guardian of immune tolerance that can reduce autoimmune disease risk by regulating IL7R splicing and upregulating FOXP3.
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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.
2021-09-01 | GSE178992 | GEO
Project description:Regulatory T (Treg) cells are important regulators of the immune system and have versatile functions for the homeostasis and repair of tissues. They express the forkhead box transcription factor Foxp3 as a lineage-defining protein. In mature Treg cells, the Foxp3 core promoter is unmethylated indicating that this area could harbor a transcription factor complex to initiate or repress gene expression, respectively. We used an unbiased method to identify Foxp3-promoter-binding transcription factors (TFs) by inverted chromatin immunoprecipitation (IP) followed by quantitative mass spectrometry. We identified several candidate factors which showed Foxp3-promoter suppressive capacity, one of which was T-cell factor 1 (Tcf1). Using viral overexpression and CRISPR/Cas knockout studies, we identified Tcf1 as a repressor of Foxp3 expression in primary conventional CD4 T cells (Tconv). In Tcf1-deficient animals, increased levels of Foxp3intermediateCD25negative T cells were identified in secondary lymphoid tissues, implicating that Tcf1 protects Foxp3-negative T cells from inadvertent Foxp3 expression.
2020-05-26 | PXD018764 | Pride
Project description:Foxp3+ T-regulatory cells (Tregs) are key to immune homeostasis such that their diminished numbers or function can cause autoimmunity and allograft rejection. Foxp3+ Tregs express histone/protein deacetylases (HDACs) that regulate chromatin remodeling, gene expression and protein function. Pan-HDAC inhibitors developed for oncology enhance Treg production and suppression but have limited non-oncologic applications given their broad effects. We show, using HDAC6-deficient mice and WT mice treated with HDAC6-specific inhibitors, that HDAC6 inhibition promotes Treg suppressive activity in models of inflammation and autoimmunity, including multiple forms of experimental colitis and fully MHC-incompatible cardiac allograft rejection. Many of the beneficial effects of HDAC6 targeting are also achieved by inhibition of the HDAC6-regulated protein, HSP90. Hence, selective targeting of a single HDAC isoform, HDAC6, or its downstream target, HSP90, can promote Treg-dependent suppression of autoimmunity and transplant rejection. RNA from three independent samples from magnetically separated CD4+CD25+ Treg of HDAC6 knock out, compared to wild type (C57BL6) control
2011-05-01 | E-GEOD-27896 | biostudies-arrayexpress
Project description:JAK inhibition differentially affects NK cell and ILC1 homeostasis
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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