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MiRNome and transcriptome aided pathway analysis in human regulatory T cells

ABSTRACT: Owing to their manifold immune regulatory functions, regulatory T cells (Treg) have received tremendous interests as targets for therapeutic intervention of diverse immunological pathologies or cancer. Directed manipulation of Treg will only be achievable with extensive knowledge about the intrinsic programs that define their regulatory function. We simultaneously analyzed miR and mRNA transcript levels in resting and activated human Treg cells in comparison to non-regulatory conventional T cells (Tcon). Based on experimentally validated miR-target information, both transcript levels were integrated into a comprehensive pathway analysis. This strategy revealed characteristic signal transduction pathways involved in Treg biology such as TCR-, TLR-, TGF-, JAK/STAT- and mTOR signaling and allowed for the prediction of specific pathway activities on the basis of miR and mRNA transcript levels in a probabilistic manner. These data encourage new concepts for targeted control of Treg cell effector function.

ORGANISM(S): Homo sapiens

PROVIDER: GSE54953 | GEO | 2014/05/23

SECONDARY ACCESSION(S): PRJNA238139

REPOSITORIES: GEO

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MiRNome and transcriptome aided pathway analysis in human regulatory T cells

Project description:Owing to their manifold immune regulatory functions, regulatory T cells (Treg) have received tremendous interests as targets for therapeutic intervention of diverse immunological pathologies or cancer. Directed manipulation of Treg will only be achievable with extensive knowledge about the intrinsic programs that define their regulatory function. We simultaneously analyzed miR and mRNA transcript levels in resting and activated human Treg cells in comparison to non-regulatory conventional T cells (Tcon). Based on experimentally validated miR-target information, both transcript levels were integrated into a comprehensive pathway analysis. This strategy revealed characteristic signal transduction pathways involved in Treg biology such as TCR-, TLR-, TGFM-oM-^AM-"-, JAK/STAT- and mTOR signaling and allowed for the prediction of specific pathway activities on the basis of miR and mRNA transcript levels in a probabilistic manner. These data encourage new concepts for targeted control of Treg cell effector function. Differential gene expression was measured in highly pure, FACS-sorted, resting regulatory T cells and conventional T cells and stimulated regulatory T cells and conventional T cells. Two independent experiments using pooled samples from 5 different donors were performed for each cell type and activation condition.

2014-05-23 | E-GEOD-54953 | biostudies-arrayexpress

Integrated Analysis of T-cell Repertoire and Transcriptome Shed Light into the Mechanisms of Regulatory T cell (Treg) Suppression of Acute Graft-versus-Host-Disease

Project description:CD4+ FOXP3+ regulatory T (Treg) cells are currently under clinical evaluation as an immunoregulatory cellular therapy for graft-versus-host disease (GvHD) prevention and treatment. Preclinical and clinical studies indicate that Treg are able to protect from GvHD without interfering with the graft-versus-tumor (GvT) effect of hematopoietic cell transplantation (HCT), although the underlying molecular mechanisms are largely unknown. To elucidate Treg suppressive function during in vivo suppression of acute GvHD, we performed paired T cell receptor (TCR) sequencing and RNA sequencing analysis on conventional T cells (Tcon) and Treg before and after transplantation in an MHC major-mismatch mouse model of HCT. We show that both Treg and Tcon underwent clonal expansion and that Treg did not interfere with the activation of alloreactive Tcon clones. Transcriptomic analysis revealed that Treg predominantly affected CD4 Tcon and to a lesser extent CD8 Tcon transcriptome, modulating the transcription of genes encoding pro- and anti-inflammatory molecules as well as enzymes involved in metabolic processes, inducing a switch from glycolysis to oxidative phosphorylation. Finally, Treg did not interfere with the induction of gene sets involved in the GvT effect. Our results shed light into the mechanisms of acute GvHD suppression by Treg and will support the clinical translation of this immunoregulatory approach.

2022-07-15 | GSE205375 | GEO

Gene expression of cAMP-relevant genes in T cell subsets

Project description:Analysis of gene expression level of cAMP-relevant genes in non-activated murine conventional (Tcon) and regulatory T cell (Treg) subsets

2022-12-21 | GSE221135 | GEO

Pregnancy enables expansion of autoreactive regulatory T cells in an animal model of multiple sclerosis

Project description:Disease activity of autoimmune disorders such as multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) is temporarily suppressed by pregnancy. However, whether disease amelioration is due to non-specific immunomodulation or mediated by antigen-specific regulation of disease-causing conventional T cells (Tcon) and immuno- suppressive regulatory T cells (Treg), remains elusive. In the present study, we systematically analyzed changes of the T cell receptor (TCR) β repertoire driven by EAE and pregnancy using TCR sequencing. We demonstrate that EAE, but not pregnancy, robustly increased TCR repertoire clonality in both peripheral Tcon and Treg. Notably, pregnancy was required for the expansion of Treg harboring the dominant EAE-associated TRBV chain 13.2 and increased the frequency of EAE-associated clonotypes within the Treg compartment. Our findings indicate that pregnancy supports the expansion of Treg clonotypes that are equipped to recognize EAE- associated antigens. These Treg are thereby particularly suited to control corresponding encephalitogenic Tcon responses and likely contribute to pregnancy-associated protection in autoimmunity.

2019-07-30 | GSE122894 | GEO

FoxP3 and Ezh2 Regulate Tfr cell Suppressive Function and Transcriptional Program [tissue]

Project description:Tissue Specific Transcriptional Profiling of Tfh, Tfr, Treg and Tcon

2019-01-25 | GSE124883 | GEO

TNF activates a distinct cellular program in human regulatory T cells

Project description:Here we show that tumor necrosis factor (TNF) induced in human T-regulatory cells (Treg), as compared to conventional T cells (Tcon), a transcription program highly enriched for typical NF-κB target genes, such as: the cytokines LTA and TNF; the TNF-receptor super family members FAS, 4-1BB and OX-40; various anti-apoptotic genes; and other important immune-response genes. As an initial approach to examine the cellular program induced by TNF in Tregs versus Tcon cells, we employed microarray gene expression analysis at 2 and 24 hrs following TNF treatment.

2009-12-31 | GSE18893 | GEO

small RNA-Seq of miR-181 deficient Treg cells

Project description:The interdependence of selective cues during development of regulatory T (Treg) cells in the thymus and their suppressive function remains incompletely understood. Here we analyzed this interdependence by taking advantage of highly dynamic changes of miR-181a/b-1 during late T-cell development with very high levels of expression during thymocyte selection followed by massive downregulation in the periphery. Loss of miR-181a/b-1 resulted in inefficient de novo generation of Treg cells in the thymus, but simultaneiously permitted homeostatic expansion in the periphery in the absence of competition. Modulation of T-cell receptor (TCR) signal strength in vivo indicated that miR-181a/b-1 controlled Treg cell formation via establishing adequate signaling thresholds. Unexpectedly, miR-181a/b-1-deficient Treg cells displayed elevated suppressive capacity in vivo, in line with elevated levels of CTLA-4 protein, but not mRNA, in thymic and peripheral Treg cells. Therefore, we propose that intrathymic miR-181a/b-1 controls development of Treg cells and imposes a developmental legacy on their peripheral function.

2019-01-04 | GSE124594 | GEO

Excessive miR-27 expression impairs regulatory T cell-mediated immunological tolerance [CD4cre miR-23 clusterTg Tr]

Project description:MicroRNAs (miRNAs) are tightly regulated in the immune system, as aberrant expression of miRNAs often results in hematopoietic malignancies and autoimmune diseases. Previously, elevated levels of miR-27 in T cells isolated from multiple sclerosis patients has been suggested to facilitate disease progression through inhibiting Th2 immunity and promoting pathogenic Th1 responses. Here we demonstrate that while mice with T cell-specific overexpression of miR-27 harbor dysregulated Th1 responses and develop autoimmune pathology, these disease phenotypes are not driven by miR-27 in effector T cells in a cell-autonomous manner but rather resulted from a perturbed regulatory T (Treg) cell compartment. Excessive miR-27 expression in T cells severely impairs Treg cell differentiation. Moreover, Treg cells with exaggerated miR-27-mediated gene regulation exhibit diminished homeostasis and suppressor function in vivo. Mechanistically, miR-27 represses several known as well as previously uncharacterized targets that play critical roles in controlling multiple aspects of Treg cell biology. Collectively, our data show miR-27 functions as a key regulator in Treg cell development and function and suggest that proper regulation of miR-27 is pivotal to safeguard Treg cell-mediated immunological tolerance.

2016-11-05 | GSE89546 | GEO

Excessive miR-27 expression impairs regulatory T cell-mediated immunological tolerance [Foxp3cre het miR-27Tg]

2016-11-05 | GSE89547 | GEO

miR-15/16 clusters restrict effector Treg cell differentiation and function

Project description:Effector regulatory T cells (eTregs) exhibit distinct homeostatic properties and superior suppressor capacities pivotal for controlling immune responses mediated by their conventional T cell counterpart. While the role of microRNAs (miRNAs) in Tregs has been well-established, how miRNAs regulate eTregs remains poorly understood. Here, we demonstrate that miR-15/16 clusters act as key regulators in limiting eTreg responses. Loss of miR-15/16 clusters leads to increased eTreg frequencies with enhanced suppressor function. Consequently, mice with Treg-specific ablation of miR-15/16 clusters display attenuated immune responses during neuroinflammation and upon both infectious and non-infectious challenges. Mechanistically, miR-15/16 clusters exert their regulatory effect in part through repressing IRF4, a transcription factor essential for eTreg differentiation and function. Moreover, miR-15/16 clusters also directly target neuritin, an IRF4-dependent molecule, known for its role in Treg-mediated regulation of plasma cell responses. Together, we identify an miRNA family that controls an important Treg subset and further demonstrate that eTreg responses are tightly regulated at both transcriptional and posttranscriptional levels.

2023-07-21 | GSE225737 | GEO

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