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Helios enhances the preferential differentiation of human fetal CD4+ naïve T cells into regulatory T cells.

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE110472 | GEO | 2019/11/22

REPOSITORIES: GEO

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Helios enhances the preferential differentiation of human fetal CD4+ naive T cells into regulatory T cells.

Project description:T cell receptor (TCR) stimulation and cytokine cues drive the differentiation of CD4+ naïve T cells into effector T cell populations with distinct proinflammatory or regulatory functions. Unlike adult naïve T cells, human fetal naïve CD4+ T cells preferentially differentiate into FOXP3+ regulatory T (Treg) cells upon TCR activation independent of exogenous cytokine signaling. This cell-intrinsic predisposition for Treg differentiation is implicated in the generation of tolerance in utero; however, the underlying mechanisms remain largely unknown. Here, we identify epigenetic and transcriptional programs shared between fetal naïve T and committed Treg cells that are inactive in adult naïve T cells and show that fetal-derived induced Treg (iTreg) cells retain this transcriptional program. We show that a subset of Treg-specific enhancers is accessible in fetal naïve T cells, including two active superenhancers at Helios Helios is expressed in fetal naïve T cells but not in adult naïve T cells, and fetal iTreg cells maintain Helios expression. CRISPR-Cas9 ablation of Helios in fetal naïve T cells impaired their differentiation into iTreg cells upon TCR stimulation, reduced expression of immunosuppressive genes in fetal iTreg cells such as IL10, and increased expression of proinflammatory genes including IFNG Consequently, Helios knockout fetal iTreg cells had reduced IL-10 and increased IFN-γ cytokine production. Together, our results reveal important roles for Helios in enhancing preferential fetal Treg differentiation and fine-tuning eventual Treg function. The Treg-biased programs identified within fetal naïve T cells could potentially be used to engineer enhanced iTreg populations for adoptive cellular therapies.

| S-EPMC7340007 | biostudies-literature

Helios enhances the preferential differentiation of human fetal CD4+ naïve T cells into regulatory T cells. [Epigenetics]

Project description:Human fetal naïve T cells preferentially differentiate into CD25hiFOXP3hi regulatory T (Treg) cells upon T cell receptor (TCR) stimulation, which contribute to the generation of immunotolerance in the developing human fetus. We utilized ATACseq and H3K27ac ChIPseq to characterize the human fetal naive T cell epigenome relative to that of adult naive T cells and Treg cells. Fetal naive T cells share a partial Treg epigenome with increased chromatin accessibility and H3K27ac enrichment at a subset of Treg-specific enhancers.

2019-11-22 | GSE110468 | GEO

Helios enhances the preferential differentiation of human fetal CD4+ naïve T cells into regulatory T cells. [RNA-Seq - ex vivo]

Project description:RNA sequencing was used to compare the transcriptome of ex vivo isolated adult and fetal naïve and regulatory T (Treg) cells. A Treg-specific transcriptome was defined by genes upregulated and downregulated preferentially in adult and fetal Treg cells relative to adult naive T cells. Fetal naive T cells show an intermediate expression of genes in the Treg-specific transcriptome.

2019-11-22 | GSE110469 | GEO

Helios enhances the preferential differentiation of human fetal CD4+ naïve T cells into regulatory T cells [RNA-Seq - induced Treg cells].

Project description:RNA sequencing was used to compare the transcriptome of in vitro differentiated adult and fetal induced Treg (iTreg) cells that were culture with IL-2 alone or supplemented with additional TGFb. Additionally, fetal iTreg cells also had Helios knocked out by CRISPR-Cas9 editing, with paired samples treated with the Helios guide RNA1 (HeliosKO) or with the non-targeting control (HeliosWT). Differential gene expression was assessed using generalised linear model designs. This revealed that fetal iTreg cells retain a expression of Treg-specific signature previously identified to be unregulated in primary ex vivo fetal naive T cells, and this signature was not expressed by adult iTreg cells. Helios expression then regulates the Treg-specific transcriptome within fetal iTreg cells by enhancing upregulation of genes associated with Treg differentiation and function, and repressing genes associated with effector specification and pro-inflammatory function.

2019-11-22 | GSE131589 | GEO

Helios enhances the preferential differentiation of human fetal CD4+ naïve T cells into regulatory T cells.

Project description:Helios enhances the preferential differentiation of human fetal CD4+ naïve T cells into regulatory T cells.

| PRJNA433827 | ENA

Helios enhances the preferential differentiation of human fetal CD4+ naïve T cells into regulatory T cells. [Epigenetics]

Project description:Helios enhances the preferential differentiation of human fetal CD4+ naïve T cells into regulatory T cells. [Epigenetics]

| PRJNA433824 | ENA

Helios enhances the preferential differentiation of human fetal CD4+ naïve T cells into regulatory T cells. [RNA-Seq - ex vivo]

Project description:Helios enhances the preferential differentiation of human fetal CD4+ naïve T cells into regulatory T cells. [RNA-Seq - ex vivo]

| PRJNA433825 | ENA

Helios enhances the preferential differentiation of human fetal CD4+ naïve T cells into regulatory T cells [RNA-Seq - induced Treg cells].

Project description:Helios enhances the preferential differentiation of human fetal CD4+ naïve T cells into regulatory T cells [RNA-Seq - induced Treg cells].

| PRJNA544098 | ENA

Helios Deficiency Predisposes the Differentiation of CD4+Foxp3- T Cells into Peripherally Derived Regulatory T Cells.

Project description:The transcription factor Helios is expressed in a large percentage of Foxp3+ regulatory T (Treg) cells and is required for the maintenance of their suppressive phenotype, as mice with a selective deficiency of Helios in Treg cells spontaneously develop autoimmunity. However, mice with a deficiency of Helios in all T cells do not exhibit autoimmunity, despite the defect in the suppressor function of their Treg cell population, suggesting that Helios also functions in non-Treg cells. Although Helios is expressed in a small subset of CD4+Foxp3- and CD8+ T cells and its expression is upregulated upon T cell activation, its function in non-Treg cells remains unknown. To examine the function of Helios in CD4+Foxp3- T cells, we transferred Helios-sufficient or -deficient naive CD4+Foxp3- TCR transgenic T cells to normal recipients and examined their capacity to respond to their cognate Ag. Surprisingly, Helios-deficient CD4+ T cells expanded and differentiated into Th1 or Th2 cytokine-producing effectors in a manner similar to wild-type TCR transgenic CD4+ T cells. However, the primed Helios-deficient cells failed to expand upon secondary challenge with Ag. The tolerant state of the Helios-deficient memory T cells was not cell-intrinsic but was due to a small population of Helios-deficient naive T cells that had differentiated into Ag-specific peripheral Treg cells that suppressed the recall response in an Ag-specific manner. These findings demonstrate that Helios plays a role in the determination of CD4+ T cell fate.

| S-EPMC6615958 | biostudies-literature

Phenotypic and functional properties of Helios+ regulatory T cells.

Project description:Helios, an Ikaros family transcription factor, is preferentially expressed at the mRNA and protein level in regulatory T cells. Helios expression previously appeared to be restricted to thymic-derived Treg. Consistent with recent data, we show here that Helios expression is inducible in vitro under certain conditions. To understand phenotypic and functional differences between Helios(+) and Helios(-) Treg, we profiled cell-surface markers of FoxP3(+) Treg using unmanipulated splenocytes. We found that CD103 and GITR are expressed at high levels on a subset of Helios(+) Treg and that a Helios(+) Treg population could be significantly enriched by FACS sorting using these two markers. Quantitative real-time PCR (qPCR) analysis revealed increased TGF-? message in Helios(+) Treg, consistent with the possibility that this population possesses enhanced regulatory potential. In tumor-bearing mice, we found that Helios(+) Treg were relatively over-represented in the tumor-mass, and BrdU studies showed that, in vivo, Helios(+) Treg proliferated more than Helios(-) Treg. We hypothesized that Helios-enriched Treg might exert increased suppressive effects. Using in vitro suppression assays, we show that Treg function correlates with the absolute number of Helios(+) cells in culture. Taken together, these data show that Helios(+) Treg represent a functional subset with associated CD103 and GITR expression.

| S-EPMC3316700 | biostudies-literature

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