A disrupted FOXP3 transcriptional signature underpins regulatory T cells insufficiency in early pregnancy failure
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1001301 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25491500_1.fastq.gz | Fastqsanger.gz | |||
| SRR25491500_2.fastq.gz | Fastqsanger.gz | |||
| SRR25491600_1.fastq.gz | Fastqsanger.gz | |||
| SRR25491600_2.fastq.gz | Fastqsanger.gz | |||
| SRR25491501_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 410 |
Similar Datasets
Project description:Regulatory T (Treg) cell defects are implicated in disorders of embryo implantation and placental development, but the origins of Treg cell dysfunction are unknown. Here, we comprehensively analyzed the phenotypes and transcriptional profile of peripheral blood Treg cells in individuals with early pregnancy failure (EPF). Compared to fertile subjects, EPF subjects had 32% fewer total Treg cells and 54% fewer CD45RA+CCR7+ naïve Treg cells amongst CD4+ T cells, accompanied by lower Treg:Th1 and Treg:Th17 ratios. An altered phenotype with reduced transcription factor FOXP3 and suppressive marker CTLA4 was also evident. RNAseq demonstrated an aberrant gene expression profile, with upregulation of pro-inflammatory genes including CSF2, IL4, IL17A, IL21, and IFNG, in EPF Treg cells. In silico analysis revealed 25% of the Treg cell dysregulated genes are targets of FOXP3 control. We conclude that Treg cell defects in EPF can arise due to loss of lineage fidelity associated with impaired FOXP3 regulation.
2024-01-28 | GSE239865 | GEO
Project description: Not available
| S-EPMC10847744 | biostudies-literature
Project description:Regulatory T cells (Tregs) are responsible for limiting autoimmunity and chronic inflammation. Foxp3 is a transcription factor that acts as a master regulator of Treg development and function. A serendipitous observation led to the realization that a well-characterized Foxp3gfp reporter mouse, which expresses an N-terminal GFP-Foxp3 fusion protein, is a hypomorph that causes profoundly accelerated autoimmune diabetes on a NOD background. Although natural Treg development and in vitro function is not significantly altered in Foxp3gfp NOD and C57BL/6 mice, Treg fitness function in inflammatory environments is perturbed and TGF?-induced Treg development reduced. Foxp3gfpis unable to interact with the histone acetyltransferase Tip60, the histone deacetylase HDAC7, and the Ikaros family zinc finger 4, Eos, which leads to reduced Foxp3 acetylation and enhanced K48-linked polyubiquitylation. Collectively this leads to an altered transcriptional landscape and reduced Foxp3-mediated gene repression, notably at the hallmark IL-2 promoter. Loss of controlled Foxp3-driven epigenetic modification leads to Treg insufficiency that causes autoimmunity in prone environments. 16 samples overall split between 2 genotypes (wild type and Foxp3 knock in) and two cell types (Tregs and Tconv)
2012-12-07 | E-GEOD-35164 | biostudies-arrayexpress
Project description:Regulatory T cells (Tregs) are responsible for limiting autoimmunity and chronic inflammation. Foxp3 is a transcription factor that acts as a master regulator of Treg development and function. A serendipitous observation led to the realization that a well-characterized Foxp3gfp reporter mouse, which expresses an N-terminal GFP-Foxp3 fusion protein, is a hypomorph that causes profoundly accelerated autoimmune diabetes on a NOD background. Although natural Treg development and in vitro function is not significantly altered in Foxp3gfp NOD and C57BL/6 mice, Treg fitness function in inflammatory environments is perturbed and TGFβ-induced Treg development reduced. Foxp3gfpis unable to interact with the histone acetyltransferase Tip60, the histone deacetylase HDAC7, and the Ikaros family zinc finger 4, Eos, which leads to reduced Foxp3 acetylation and enhanced K48-linked polyubiquitylation. Collectively this leads to an altered transcriptional landscape and reduced Foxp3-mediated gene repression, notably at the hallmark IL-2 promoter. Loss of controlled Foxp3-driven epigenetic modification leads to Treg insufficiency that causes autoimmunity in prone environments.
2012-12-07 | GSE35164 | GEO
Project description:Immunometabolic adaptation in monocytes underpins functional changes during pregnancy. [MYELOID]
| PRJNA1074330 | ENA
Project description:Immunometabolic adaptation in monocytes underpins functional changes during pregnancy [metabolism]
| PRJNA1074320 | ENA
Project description:Regulatory T cells 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 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. ATP was secreted by both T effector and regulatory T cells and was reduced by mitochondrial respiration inhibitors. Thus Foxp3 imparts a selective advantage in ATP generation capacity to the cell and may exploit this as a source of adenosine for functional immunomodulation. In order to explore possible mechanisms for these differences in metabolism we conducted a comparative 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 T cells and Foxp3 positive iTreg and Foxp3 negative activated CD4 T cells in addition to human peripheral blood natural Treg. Gene set enrichment analysis of our proteomic datasets demonstrated that Foxp3 drives a significant up regulation of several members of the mitochondrial electron transport chain.
2017-02-15 | PXD001789 | Pride
Project description:Metabolic heterogeneity is a determinant of immune cell function. The normal physiological metabolic reprogramming of pregnancy that ensures the fuel requirements of mother and baby are met might also underpin changes in innate and adaptive immunity that occur with pregnancy and manifest as altered responses to pathogens and changes to autoimmune disease symptoms. Here, we use peripheral blood monocytes, susceptible to microenvironmentally determined reprogramming of metabolism, to determine if pregnancy at term provokes an altered metabolic profile that underpins functional change. Focusing on late gestation where any effect will be most profound, we reveal that monocytes lose M2-like and gain M1-like properties accompanied by reductions in mitochondrial mass, maximal respiration and cardiolipin content in pregnancy; glycolysis is unperturbed. We establish that muramyl dipeptide (MDP)-stimulated cytokine production relies on oxidative metabolism then show that reduced monocyte oxidative metabolism with pregnancy compromises the production of TNF and IL-6 in response to MDP but not LPS. Overall, mitochondrially centred metabolic capabilities of late gestation monocytes are downregulated revealing natural plasticity in monocyte phenotype and function that could reveal targets for improving pregnancy outcomes but also yield new therapeutic approaches to diverse metabolic and/or immune-mediated diseases beyond pregnancy.
2024-04-01 | GSE255271 | GEO
Project description:Metabolic heterogeneity is a determinant of immune cell function. The normal physiological metabolic reprogramming of pregnancy that ensures the fuel requirements of mother and baby are met might also underpin changes in innate and adaptive immunity that occur with pregnancy and manifest as altered responses to pathogens and changes to autoimmune disease symptoms. Here, we use peripheral blood monocytes, susceptible to microenvironmentally determined reprogramming of metabolism, to determine if pregnancy at term provokes an altered metabolic profile that underpins functional change. Focusing on late gestation where any effect will be most profound, we reveal that monocytes lose M2-like and gain M1-like properties accompanied by reductions in mitochondrial mass, maximal respiration and cardiolipin content in pregnancy; glycolysis is unperturbed. We establish that muramyl dipeptide (MDP)-stimulated cytokine production relies on oxidative metabolism then show that reduced monocyte oxidative metabolism with pregnancy compromises the production of TNF and IL-6 in response to MDP but not LPS. Overall, mitochondrially centred metabolic capabilities of late gestation monocytes are downregulated revealing natural plasticity in monocyte phenotype and function that could reveal targets for improving pregnancy outcomes but also yield new therapeutic approaches to diverse metabolic and/or immune-mediated diseases beyond pregnancy.
2024-04-01 | GSE255273 | GEO
Project description:Metabolic heterogeneity is a determinant of immune cell function. The normal physiological metabolic reprogramming of pregnancy that ensures the fuel requirements of mother and baby are met might also underpin changes in innate and adaptive immunity that occur with pregnancy and manifest as altered responses to pathogens and changes to autoimmune disease symptoms. Here, we use peripheral blood monocytes, susceptible to microenvironmentally determined reprogramming of metabolism, to determine if pregnancy at term provokes an altered metabolic profile that underpins functional change. Focusing on late gestation where any effect will be most profound, we reveal that monocytes lose M2-like and gain M1-like properties accompanied by reductions in mitochondrial mass, maximal respiration and cardiolipin content in pregnancy; glycolysis is unperturbed. We establish that muramyl dipeptide (MDP)-stimulated cytokine production relies on oxidative metabolism then show that reduced monocyte oxidative metabolism with pregnancy compromises the production of TNF and IL-6 in response to MDP but not LPS. Overall, mitochondrially centred metabolic capabilities of late gestation monocytes are downregulated revealing natural plasticity in monocyte phenotype and function that could reveal targets for improving pregnancy outcomes but also yield new therapeutic approaches to diverse metabolic and/or immune-mediated diseases beyond pregnancy.
2024-04-26 | PXD050094 | Pride