Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Deletion of a Distal IRF4 Element Prevents Inflammation-induced Reprogramming of Human Regulatory T-cell Fate

ABSTRACT: Adoptive regulatory T cell (Treg) therapy is an emergent treatment paradigm in which ex vivo-expanded Tregs are administered to promote immune tolerance in transplant and autoimmune disease patients. While preclinical models have demonstrated remarkable efficacy, lineage-tracing studies have also revealed that chronic inflammatory exposures can cause a subset of murine Tregs to undergo Foxp3 downregulation and epigenetic reprogramming toward a dysfunctional, proinflammatory state. Despite the potential ramifications for clinical translation, whether human Tregs exhibit a similar susceptibility to inflammatory cytokine-mediated lineage decommitment remains inconclusive. Here, we present an in vitro model of human Treg destabilization characterized by FOXP3 downregulation, Treg-specific demethylated region (TSDR) re-methylation, loss of suppressive activity, and gain of proinflammatory functions. Analysis of single-cell ATAC and transcriptomic profiles from destabilized Tregs revealed a switch in chromatin accessibility between two elements at the IRF4 locus. Excision of the distal IRF4 element enabled Tregs to resist inflammatory cytokine-induced reprogramming, presenting a potential strategy to design more effective Treg therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE281099 | GEO | 2026/08/05

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Mbd2 promotes Foxp3 demethylation and T-regulatory cell function

Project description:The proposed use of Foxp3+ T-regulatory (Treg) cells as potential cellular therapy in patients with autoimmune diseases, or post-hemopoietic stem cell or organ transplantation, requires a sound understanding of the transcriptional regulation of Foxp3 expression. Conserved CpG dinucleotides in the Treg-specific demethylated region (TSDR) upstream of Foxp3 are demethylated only in stable, thymic-derived Foxp3+ Tregs. Since methyl-binding domain (Mbd) proteins recruit histone-modifying and chromatin-remodeling complexes to methylated sites, we tested whether targeting of Mbd2 might promote demethylation of Foxp3 and thereby promote Treg numbers or function. Surprisingly, while ChIP analysis showed Mbd2 binding to the Foxp3-associated TSDR site in Tregs, Mbd2 targeting by homologous recombination or siRNA decreased Treg numbers and impaired Treg suppressive function in vitro and in vivo. Moreover, we found complete TSDR demethylation in WT Tregs but >75% methylation in Mbd2-/- Tregs, whereas re-introduction of Mbd2 into Mbd2-null Tregs restored TSDR demethylation, Foxp3 gene expression and Treg suppressive function. Lastly, Mbd2-/- Tregs had markedly binding of the DNA demethylase enzyme, Tet2, in the TSDR region. These data show that Mbd2 has a key role in promoting TSDR demethylation, Foxp3 expression and Treg suppressive function. RNA from three independent samples from magnetically separated CD4+CD25+ Treg of MBD2–/– mice, compared to wild type control (all Balb/c background).

2013-09-01 | E-GEOD-48653 | biostudies-arrayexpress

Deletion of a Distal IRF4 Element Prevents Inflammation-induced Reprogramming of Human Regulatory T-cell Fate

Project description:Adoptive regulatory T cell (Treg) therapy is an emergent treatment paradigm for restoring immune tolerance in patients with autoimmune and inflammatory diseases. While preclinical models have demonstrated the remarkable efficacy of Treg cell therapy, lineage-tracing studies have also revealed that murine Tregs can lose lineage identity and adopt a proinflammatory state. Whether human Tregs exhibit a similar susceptibility to inflammatory cytokine-mediated lineage decommitment remains inconclusive. Here, we present an in vitro model of human Treg destabilization characterized by silencing of the Treg lineage-defining transcription factor, FOXP3, loss of suppressive activity, and gain of proinflammatory functions. Analysis of single-cell ATAC and transcriptomic profiles of Tregs during destabilization revealed a switch in chromatin accessibility between two elements at the IRF4 locus. Excision of the distal IRF4 element enabled Tregs to resist inflammatory cytokine-induced reprogramming, presenting a cell-engineering strategy to design more effective Treg therapies.

2026-08-03 | GSE331192 | GEO

Mbd2 promotes Foxp3 demethylation and T-regulatory cell function

2013-09-01 | GSE48653 | GEO

Critical Requirement of the DNA Methyltransferase, Dnmt1, for the Development and Function of Foxp3+ Regulatory T Cells

Project description:We investigated the role of DNMT1 in immune homeostasis by generating mice lacking DNMT1 in Foxp3+ T-regulatory (Treg) cells. These mice showed decreased peripheral Foxp3+ Tregs, complete loss of Foxp3+ Treg suppressive functions in vitro and in vivo, and died from autoimmunity by 3-4 weeks unless they received perinatal transfer of wild-type Tregs that prolonged their survival. Methylation of CpG-sites in the TSDR region of Foxp3 was unaffected by DNMT1 deletion, but microarray revealed more >500 proinflammatory and other genes were upregulated in DNMT1-/- Tregs. CD4-Cre-mediated DNMT1 deletion showed inability of conventional T cells to convert to Foxp3+ Treg under appropriate polarizing conditions. Hence, DNMT1 is absolutely necessary for maintenance of the gene program required for normal Treg development and function. RNA from three independent samples of magnetically separated CD4+CD25+ Treg of fl-DNMT1/Foxp3cre mice, compared to wild type (C57BL6) control

2013-04-21 | E-GEOD-27434 | biostudies-arrayexpress

Critical Requirement of the DNA Methyltransferase, Dnmt1, for the Development and Function of Foxp3+ Regulatory T Cells

2013-04-21 | GSE27434 | GEO

RNA-Seq of human regulatory T cells and effector T cells cultured at standard 37C temperature and in mild hypothermia (33C).

Project description:Regulatory T cells (Tregs) play crucial role in maintenance of peripheral tolerance. Numerous clinical trials confirmed safety and efficacy of Treg treatment of for deleterious immune responses. However, Tregs lose their characteristic phenotype and suppressive potential during expansion ex vivo. In our experiment we demonstrate that mild hypothermia of 33C induces robust proliferation of human Tregs, preserves expression of FoxP3, CD25 and Helios, and prevents TSDR methylation during culture in vitro. Tregs expanded at 33C showed stronger immunosuppressive potential and anti-inflammatory phenotype. We show that a simple change in temperature can preserve Treg stability, function and accelerate their proliferation in vitro.

2017-10-04 | E-MTAB-5322 | biostudies-arrayexpress

IL-27 stimulation in Foxp3+ Tregs improves suppressive function and therapeutic efficacy

Project description:Foxp3 expressing regulatory T cells (Tregs) are the central regulator of immune homeostasis and tolerance. As it is believed that proper Treg function is compromised under inflammatory conditions, exploring a pathway that enhances Treg function is of great importance. In this study, we report that IL-27, an IL-12 family cytokine known to play both pro- and anti-inflammatory role in T cells, plays a pivotal role in Treg function to control T cell-induced colitis. Unlike WT Tregs capable of inhibiting colitogenic T cell expansion and inflammatory cytokine expression, IL-27R-deficient Tregs were unable to downregulate inflammatory T cell responses. Tregs stimulated with IL-27 expressed substantially enhanced suppressive function both in vitro and in vivo. IL-27 stimulation of Tregs induced expression of LAG3, a surface molecule implicated in negatively regulating immune responses. LAG3 expression in IL-27-stimulated Tregs was critical to mediate suppressive Treg function. Finally, human Tregs also displayed enhanced suppressive function and LAG3 expression in response to IL-27 stimulation. Taken together, our results highlight a novel function of the IL-27/LAG3 axis in Treg regulation of inflammatory responses in the intestine. FACS purified Foxp3+ Tregs were stimulated in the presence of media or IL-27 to compare IL-27 induced gene profiles. Four samples (media stimulated or IL-27-stimulated) were collected from four independent experiments. Genes altered by IL-27 treatment were compared to those of media stimulated Tregs.

2015-11-01 | E-GEOD-63455 | biostudies-arrayexpress

Targeted de-methylation of the FOXP3-TSDR

Project description:CD4+ regulatory T cells (Tregs) are key mediators of immunological tolerance and promising effector cells for immuno-suppressive adoptive cellular therapy to fight autoimmunity and chronic inflammation. Their functional stability is critical for their clinical utility and has been correlated to the demethylated state of the TSDR/CNS2 enhancer element in the Treg lineage transcription factor FOXP3. However, proof for a causal contribution of the TSDR de-methylation to FOXP3 stability and Treg induction is so far lacking. We here established a powerful transient-transfection CRISPR-Cas9-based epigenetic-editing method for the selective de-methylation of the TSDR within the endogenous chromatin environment of a living cell. The induced de-methylated state was stable over weeks in clonal T cell proliferation cultures even after expression of the editing complex had ceased. Epigenetic editing of the TSDR resulted in FOXP3 expression, even in its physiological isoform distribution, proving a causal role for the de-methylated TSDR in FOXP3 regulation. However, successful FOXP3 induction was not associated with a switch towards a functional Treg phenotype, in contrast to what has been reported from FOXP3 overexpression approaches. Thus, TSDR de-methylation is required, but not sufficient for a stable Treg phenotype induction. Therefore, targeted demethylation of the TSDR may be a critical addition to published in vitro Treg induction protocols which so far lack FOXP3 stability.

| EGAS00001004867 | EGA

The DEL-1–β3 integrin axis promotes Runx-1–dependent Foxp3 expression and regulatory T cell responses at mucosal barrier sites

Project description:Foxp3+CD4+ regulatory T cells (Tregs) are critical for immune homeostasis and respond to local tissue cues, which control their stability and function. We explored here whether DEL-1, which, like Tregs, increases during resolution of inflammation, promotes Treg responses. DEL-1 enhanced Treg numbers and function at barrier sites (oral and lung mucosa). The underlying mechanism was dissected using mice lacking DEL-1 or expressing a point mutant thereof, or mice with CD4-specific deletion of the transcription factor Runx1, identified by RNA-seq analysis of the DEL-1-induced Treg transcriptome. Specifically, through interaction with avβ3-integrin, DEL-1 promoted induction of Runx1-dependent Foxp3 expression and conferred stability of Foxp3 expression upon Treg restimulation in the absence of exogenous TGFβ1. Additionally, DEL-1 increased RUNX1 and FOXP3 expression in human conventional T cells promoting their conversion into induced Tregs with increased TSDR demethylation, increased stability and suppressive activity. We thus uncovered a DEL-1-avβ3-Runx1 axis that promotes Treg responses at barrier sites and offers novel therapeutic options for modulating inflammatory/autoimmune disorders.

2020-12-31 | GSE131315 | GEO

Mitochondrial regulator CRIF1 deficiency induces Foxp3low inflammatory non-suppressive regulatory-T cells in tumors [ATAC-seq]

Project description:Foxp3low inflammatory non-suppressive (INS)-regulatory T cells (Tregs) were discovered recently. Unlike conventional Tregs, they produce proinflammatory-cytokines, exhibit reduced suppressiveness, and promote rather than impair anti-tumor immunity. The role of mitochondria in Foxp3low INS-Treg formation in vivo is unclear. We showed that the Foxp3low INS-Treg equivalents in human tumors demonstrate attenuated expression of CRIF1, a vital mitochondrial regulator. Mice with CRIF1 deficiency in Tregs bore Foxp3low INS-Tregs with mitochondrial dysfunction. The -ketoglutarate-mTORC1 axis was enhanced in these cells. This promoted proinflammatory-cytokine expression by inducing EOMES and SATB1 expression. Moreover, chromatin openness of the regulatory regions of the Ifng and Il4 genes was increased, which facilitated EOMES/SATB1 binding. The increased -ketoglutarate-derived 2-hydroxyglutarate downregulated Foxp3 expression by methylating the Foxp3-gene regulatory regions. Furthermore, CRIF1-deficiency-induced Foxp3low INS-Tregs suppressed tumor growth in an IFN- dependent manner. Thus, CRIF1-mediated mitochondrial homeostasis is critical for inducing Foxp3low INS-Tregs that promote anti-tumor immunity.

2024-02-28 | GSE233902 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data