Transmembrane TNF-TNFR2 axis promotes generation of human T cell precursors
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA743519 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR15035002.fastq.gz | Fastqsanger.gz | |||
| SRR15035004.fastq.gz | Fastqsanger.gz | |||
| SRR15035006.fastq.gz | Fastqsanger.gz | |||
| SRR15035008.fastq.gz | Fastqsanger.gz |
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Project description:Transmembrane TNF-TNFR2 axis promotes generation of human T cell precursors
| PRJNA744161 | ENA
Project description:Transmembrane TNF-TNFR2 axis promotes generation of human T cell precursors.
| PRJNA870102 | ENA
Project description:The goal of this study is to dissect the impact of soluble (sTNF) and transmembrane (tmTNF) forms of tumour necrosis factor on the differentiation of human hematopoietic stem and progenitor cells (HSPCs) into T cell precursors. To achieve this, we utilized scRNA-sequencing technologies to compare the transcriptome profiles of HSPCs that had been differentiated in the artificial thymic organoid (ATO) system in the absence (control) or presence of TNF signal (soluble or transmembrane).
2022-12-12 | GSE211400 | GEO
Project description:The goal of this study is to understand how low level of IRF8 expression promotes the differentiation of human hematopoietic stem and progenitor cells (HSPCs) into T cell precursors. To achieve this, we utilized a construct that encodes IRF8-ERT2 fusion protein where IRF8 activity is tamoxifen-dependent. We extracted genomic DNA from HSPCs that had been co-cultured with OP9-DLL4 stromal cells and tagmented by Tn5 transposase for ATAC-sequencing. This allowed us to determine the impact of low level of IRF8 activity on the chromatin accessibility landscape of differentiating HSPCs. Our analysis found significant opening of chromatin region at the TNF core promoter in the presence of low level of IRF8 activity.
2022-12-11 | GSE179534 | GEO
Project description:The goal of this study is to understand how low level of IRF8 expression promotes the differentiation of human hematopoietic stem and progenitor cells (HSPCs) into T cell precursors. To achieve this, we utilized a construct that encodes IRF8-ERT2 fusion protein where IRF8 activity is tamoxifen-dependent. We extracted total RNA from transduced HSPCs that had been co-cultured with OP9-DLL4 stromal cells and treated with or without 4-hydroxytamoxifen (4-OHT) for sequencing. This allowed us to determine the impact of low level of IRF8 activity on the transcriptome profile of differentiating HSPCs. Our analysis found significant increase of TNF expression in the presence of low level of IRF8 activity.
2022-12-11 | GSE179381 | GEO
Project description:Objectives: TNF-induced activation of fibroblast-like synoviocytes (FLS) is a critical determinant for synovial inflammation and joint destruction in rheumatoid arthritis (RA). The detrimental role of TNF-receptor 1 (TNFR1) has thoroughly been characterized. The contributions of TNFR2, however, are largely unknown. This study was performed to delineate the role of TNFR2 in human FLS activation. Methods: TNFR2 expression in synovial tissue samples was determined by immunohistochemistry. Expression of TNFR2 was silenced using RNAi or CRISPR/Cas9 technologies. Global transcriptional changes were determined by RNA-seq. QPCR, ELISA and immunoblotting were used to validate RNA-seq results and to uncover pathways operating downstream of TNFR2 in FLS. Results. TNFR2 expression was increased in RA when compared to OA synovial tissues. In particular, RA-FLS demonstrated higher levels of TNFR2 when compared to OA-FLS. TNFR2 expression in RA-FLS correlated with RA disease activity, synovial T- and B-cell infiltration. TNF and IL1 were identified as inflammatory mediators that upregulate TNFR2 in RA-FLS. Silencing of TNFR2 in RA-FLS markedly diminished the TNF-induced expression of inflammatory cytokines and chemokines, including CXCR3-binding chemokines and the B-cell activating factor TNFSF13B. Immunobiochemical analyses revealed that TNFR2-mediated expression of inflammatory mediators critically depends on STAT1. Conclusion: Our results define a critical role for TNFR2 in FLS-driven inflammation and unfold its participation in the unresolved course of synovial inflammation in RA.
2022-04-26 | GSE195557 | GEO
Project description:In MS pathophysiology, soluble tumor necrosis factor (TNF) has been attributed detrimental functions, whereas transmembrane TNF promotes neurorepair primarily by activating TNF receptor 2 (TNFR2). Here we investigate the role of TNFR2 in microglia and peripheral monocyte/macrophages in EAE using novel cell-specific conditional knockouts. We show that microglial TNFR2 ablation leads to early onset of EAE, with increased CNS leucocyte infiltration, T cell activation, and demyelination. TNFR2-ablated microglia shows a more pro-inflammatory phenotype, with dysregulation of genes controlling innate immunity and host defense. Conversely, monocyte/macrophagial TNFR2 ablation results in EAE suppression, with impaired peripheral T cell activation. Our work uncovers a dichotomy of function for TNFR2 in myeloid cells, with microglial TNFR2 providing protective signals to contain disease, and monocyte/macrophagial TNFR2 driving immune activation and EAE initiation. This needs to be taken into account when targeting TNFR2 for therapeutic purposes in neuroinflammatory diseases to which both populations are key contributors.
2016-11-21 | GSE78082 | GEO
Project description:Natural Killer (NK) cells are predominant innate lymphocytes that provide the early response during infection. NK cells undergo metabolic switch to fuel augmented proliferation and activation following infection. TNFα is a well-known inammatory cytokine that enhances NK cell function, however, a mechanism for stimulation is not well established. Here, we demonstrated that upon infection/inammation, NK cells upregulate the expression of TNF receptor 2 (TNFR2), which is associated with increased proliferation, metabolic activity and effector function. Notably, IL-18 can induce TNFR2 on NK cells, augmenting their sensitivity towards TNFα. Mechanistically, TNFα-TNFR2 signaling induces CD25 (IL-2Rα) expression on NK cells predominantly by autocrine mode, leading to a metabolic switch towards aerobic glycolysis. Accordingly, genetic ablation of TNFR2 curtails the CD25 upregulation and TNFα-induced glycolysis, leading to impaired NK cell proliferation during MCMV infection in vivo. Collectively, our results delineate the crucial role of the TNFα-TNFR2 axis in NK cells for proliferation, glycolysis, and effector function via CD25 induction.
2023-09-26 | GSE235545 | GEO
Project description:PURPOSE: The goal of this study was to determine the gene expression networks regulated by tumor necrosis factor receptor 2 (TNFR2, or Tnfrsf1b) and to evaluate their potential bearing on immune cell subsets and inflammatory bowel disease (IBD). METHODS: mRNA-seq was performed on isolated distal colons from TNFR2-knockout and wildtype mice. Differentially expressed transcripts were compared to human ulcerative colitis microarray datasets on Gene Expression Omnibus and to mouse immunological expression datasets at the Immunological Genome Project. RESULTS: We identified 252 mouse transcripts whose expressions were significantly altered by the loss of TNFR2. The majority of these transcripts (228 of 252, ~90%) were downregulated in TNFR2-/- colons. TNFR2-regulated genes were able to positively discriminate between ulcerative colitis patients and healthy individuals with ~80% accuracy. Many TNFR2-regulated genes were also highly expressed in CD8+ T cells. CONCLUSIONS: Downregulation of TNFR2 is associated with a gene expression profile that is prominent in IBD and supportive of the role of CD8+ T cells in IBD pathogenesis. MANUSCRIPT ABSTRACT: Increased tumor necrosis factor (TNF) production has been associated with inflammatory bowel disease (IBD), and anti-TNF therapy is a common therapeutic for this patient population. However, the role of TNF or its receptors (TNFR1 and TNFR2) in the immunopathogenesis of inflammatory bowel disease (IBD) remains unclear. Here we report that TNFR2 is protective in spontaneous (IL-10 knockout) and chemically (azoxymethane/dextran sodium sulfate)-induced mouse models of colitis and colitis-associated cancer. Mechanistically, TNFR2-deficiency in hematopoietic cells significantly increased incidence and severity of colitis and colitis-associated cancer characterized by a selective expansion of CD8+ T cells. We identified TNFR2-regulated genes in the colon that were specific for CD8+ T cells, interacted with multiple IBD risk genes, and are important regulators of CD8+ T cell biology. TNFR2 regulated CD8+ T-cell-specific genes that act as genetic susceptibility modifiers for IBD to mitigate the development of a pro-colitogenic milieu. Antibody-mediated depletion of CD8+ T cells prevented colonic inflammation and significantly reduced pathology in IL10-/-/TNFR2-/- deficient mice. Furthermore, adoptive transfer of TNFR2-/- naïve CD8+ T cells resulted in more severe disease than with wildtype naïve CD8+ T cells. Our findings provide insight into the disease modifier role of TNFR2 in the immunopathogenesis of IBD through the modulation of CD8+ T cell responses and support future investigation of this therapeutic target, especially in the subset of IBD patients with CD8+ T-cell dysfunction. Total RNA from distal colons of 8 week-old male wildtype C57Bl/6 and TNFR2-/- mice (n=3 each) was isolated using the PureLink RNA kit (Ambion, Life Technologies). RNA samples were submitted to the Genomic Services Lab at the HudsonAlpha Institute for Biotechnology (Huntsville, AL) for multiplex library preparation, mRNA enrichment, and sequencing. Sequencing was performed to an average depth of 50M paired-end 50bp reads per sample (HiSeq, Illumina, San Diego, CA). Data files containing raw reads were aligned to the mouse genome using Tophat2/Bowtie2. Alignments were assembled into transcript representations with Cufflinks, and statistical tests for differential expression were performed with Cuffdiff 2. An adjusted P value < 0.05 (q<0.05) from the Cuffdiff 2 output was used as the cutoff for statistical significance.
2015-08-11 | E-GEOD-65408 | biostudies-arrayexpress
Project description:Multiple sclerosis (MS) is a neuroimmune disorder characterized by inflammation, CNS demyelination, and progressive neurodegeneration. Chronic MS patients exhibit impaired remyelination capacity, partly due to the changes that oligodendrocyte precursor cells (OPCs) undergo in response to the MS lesion environment. The cytokine tumor necrosis factor (TNF) is present in the MS affected CNS and has been implicated in disease pathophysiology. Of the two active forms of TNF, transmembrane (tmTNF) and soluble (solTNF), tmTNF signals via TNFR2 mediating protective and reparative effects, including remyelination, whereas solTNF signals predominantly via TNFR1 promoting neurotoxicity. To better understand the mechanisms underlying repair failure in MS, we investigated the cellular responses of OPCs to inflammatory exposure and the specific role of TNFR2 signaling in their modulation. Following treatment of cultured OPCs with IFNg, IL1b and TNF we observed by RNA sequencing marked inflammatory and immune activation of OPCs, accompanied by metabolic changes and dysregulation of their proliferation and differentiation programming. We also established the high likelihood of cell-cell interaction between OPCs and microglia in neuroinflammatory conditions, with OPCs able to produce chemokines that can recruit and activate microglia. Importantly, we showed that these functions are exacerbated when TNFR2 is ablated. Together, our data indicate that neuroinflammation leads OPCs to shift towards an immunomodulatory phenotype while diminishing their capacity to proliferate and differentiate, thus impairing their repair function. Furthermore, we demonstrated that TNFR2 plays a key role in this process, suggesting that boosting TNFR2 activation or its downstream signals could be an effective strategy to restore OPC reparative capacity in demyelinating disease.
2021-07-28 | GSE180604 | GEO