Sclerotic-type chronic graft-versus-host disease exhibits enrichment of Th1 and TSLP-OX40 cytokines
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ABSTRACT:
PROVIDER: PRJNA957821 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24233902.fastq.gz | Fastqsanger.gz | |||
| SRR24233903.fastq.gz | Fastqsanger.gz | |||
| SRR24233904.fastq.gz | Fastqsanger.gz | |||
| SRR24233905.fastq.gz | Fastqsanger.gz | |||
| SRR24233906.fastq.gz | Fastqsanger.gz |
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Project description:In this study we performed the first global RNA-seq analysis in pediatric to young-adult patients with sclerotic-type graft-versus-host disease/scGvHD (n=7), age- and sex-matched to 8 healthy controls and 10 patients with atopic dermatitis/AD. Differentially expressed genes (DEGs) were defined based on fold changes/FCH>1.5 and false discovery rate/FDR<0.05 criteria. We found robust and significant Th1 (e.g. CXCR9/10/11, IFNG) and OX40-skewing in ScGvHD (e.g. OX40L, TLSP, IL-33) that sometimes exceeded that in AD and was validated on RT-PCR.
2023-10-11 | GSE230200 | GEO
Project description:Thymic stromal lymphopoietin (TSLP) is a type I cytokine that plays a central role in induction of allergic inflammatory responses. Its principal targets have been reported to be dendritic cells and / or CD4 T cells; epithelial cells are a principal source. We report here the development of a reporter mouse (TSLP-ZsG) in which a ZsGreen (ZsG)-encoding construct has been inserted by recombineering into a bacterial artificial chromosome (BAC) immediately at the translation initiating ATG of TSLP. The expression of ZsG by mice transgenic for the recombinant BAC appears to be a faithful surrogate for TSLP expression, particularly in keratinocytes and medullary thymic epithelials cells (mTECs). A comparison of gene expression in ZsG expressing and ZsG negative mTECs and cortical thymic epithelial cells, which are all ZsG negative, revealed that all three populations can be distinguished from one another. In particular ZsG (and TSLP) expressing mTECs and ZsG- mTECs are separable populations based on gene expression profiling. Little or no expression of ZsG is observed in bone marrow-derived mast cells or basophils or in CD45+ cells infiltrating TSLP/ZsG-expressing skin. Using the TSLP-ZsG reporter mouse, we show that TNFa and IL-4/IL-13 are potent inducers of TSLP expression by keratinocytes and that local activation of Th2 and Th1 cells induces keratinocyte TSLP expression. We suggest that the capacity of TSLP to both induce Th2 differentiation and to be induced by activated Th2 cells raises the possibility that TSLP may be involved in a positive feedback loop to enhance allergic inflammatory conditions.
2015-01-06 | GSE54343 | GEO
Project description:Regulatory T (Treg) maintain the tumor microenvironment in an immunosuppressive state preventing effective anti-tumor immune response. A possible strategy to overcome Treg cell suppression focuses on OX40, a costimulatory molecule expressed constitutively by Treg cells while induced in activated effector T (Teff) cells. OX40 stimulation by the agonist mAb OX86 inhibits Treg cell suppression and boosts Teff cell activation. Here we uncover the mechanisms underlying the therapeutic activity of OX86 treatment dissecting its distinct effects on Treg and on effector memory T (Tem) cells, which are the most abundant CD4+ populations strongly expressing OX40 at the tumor site. In response to OX86, tumor-infiltrating Treg cells produced significantly less interleukin 10 (IL-10), possibly in relation to a decrease in the transcription factor IRF1. Tem cells responded to OX86 by upregulating surface CD40L expression, providing a licensing signal to dendritic cells (DCs). The CD40L/CD40 axis was required for Tem cell-mediated in vitro DC maturation and in vivo DC migration. Accordingly, OX86 treatment was no longer therapeutic in CD40 KO mice. In conclusion, following OX40 stimulation, blockade of Treg cell suppression and enhancement of the Tem cell adjuvant effect both concurred to free DCs from immunosuppression and to activate the immune response against the tumor. Total RNA obtained from sorted mouse FoxP3-GFP+ Treg activated in vitro with anti-CD3 in the presence of an OX40-agonist mAb (OX86) or isotype control.
2011-09-25 | E-GEOD-32373 | biostudies-arrayexpress
Project description:The ontogeny of human Langerhans cells (LCs) remains poorly characterized, in particular the nature of LC precursors and the factors that may drive LC differentiation. Through a systematic transcriptomic analysis of TSLP-activated dendritic cells (DCs), we unexpectedly identified markers that have been associated with a skin-homing potential as well as with a LC phenotype. We performed transcriptomic analysis of TSLP-activated blood DCs, as compared to freshly purified, Medium-, and TNF-activated DCs. Among TSLP up-regulated genes, we identified molecules associated with skin homing, LC phenotype, and LC function, as determined by a literature-based survey. Conversely, genes not expressed in LCs were not found among TSLP-induced genes. Further experiments showed that TGF-? synergized with TSLP leading to the differentiation of blood BDCA-1+ DCs into bona fide Birbeck granule-positive LCs. The ontogeny of human Langerhans cells (LCs) remains poorly characterized, in particular the nature of LC precursors and the factors that may drive LC differentiation. Through a systematic transcriptomic analysis of TSLP-activated dendritic cells (DCs), we unexpectedly identified markers that have been associated with a skin-homing potential as well as with a LC phenotype. We performed transcriptomic analysis of TSLP-activated blood DCs, as compared to freshly purified, Medium-, and TNF-activated DCs. Among TSLP up-regulated genes, we identified molecules associated with skin homing, LC phenotype, and LC function, as determined by a literature-based survey. Conversely, genes not expressed in LCs were not found among TSLP-induced genes. Further experiments showed that TGF-? synergized with TSLP leading to the differentiation of blood BDCA-1+ DCs into bona fide Birbeck granule-positive LCs. Dendritic cells (DC) were purified from the blood of healthy human donors. Each replicate comes from a different donor. There are 6 freshly purified samples (Control_0h), 4 DC samples cultured during 6h with no additional stimulus than the medium (Control_6h), 5 samples cultured during 6h with recombinant TSLP (Thymic Stromal Lymphopoietin at 20 ng/uL) (TSLP_6h) and 3 samples cultured during 6h with recombinant TNF (Tumor necrosis factor at 20 ng/mL) (TNF_6h).
2014-08-01 | E-GEOD-59237 | biostudies-arrayexpress
Project description:Atopic dermatitis (AD) is a pruritic and inflammatory disorder characterized by elevated levels of thymic stromal lymphopoietin (TSLP). Pruritus is prevalent in epidermolysis bullosa (EB). Currently, epidermal barrier disruption is known to trigger TSLP upregulation, however, mechanisms controlling TSLP expression remain incompletely understood. Tslp levels were highly upregulated in the epidermis and in the serum of keratin-deficient mice. Cultured keratinocytes either lacking keratins or expressing the dominant K14p.Arg131Pro show highly increased TSLP. Re-expression of wild-type K14 normalized TSLP levels. We demonstrate that keratins regulate Tslp expression in parts through MEK1/2 activation. The finding that 8 out of 17 EBS patients show elevated TSLP serum levels supports a major role of keratins in TSLP regulation. Our data identify a novel, keratin-dependent and cell-intrinsic regulation of Tslp. Elevated TSLP levels likely explain the high prevalence of pruritus in EBS and additional forms of EB, suggesting TSLP as novel biomarker for pruritus in EB. MEK1/2, in addition to calcineurin inhibitors, might be suitable drugs to treat itch in EB. Investigation was carried out using Keratin deficient keratinocytes isolated from typeI keratin mice.
2016-03-26 | E-GEOD-79596 | biostudies-arrayexpress
Project description:The ontogeny of human Langerhans cells (LCs) remains poorly characterized, in particular the nature of LC precursors and the factors that may drive LC differentiation. Through a systematic transcriptomic analysis of TSLP-activated dendritic cells (DCs), we unexpectedly identified markers that have been associated with a skin-homing potential as well as with a LC phenotype. We performed transcriptomic analysis of TSLP-activated blood DCs, as compared to freshly purified, Medium-, and TNF-activated DCs. Among TSLP up-regulated genes, we identified molecules associated with skin homing, LC phenotype, and LC function, as determined by a literature-based survey. Conversely, genes not expressed in LCs were not found among TSLP-induced genes. Further experiments showed that TGF-β synergized with TSLP leading to the differentiation of blood BDCA-1+ DCs into bona fide Birbeck granule-positive LCs. The ontogeny of human Langerhans cells (LCs) remains poorly characterized, in particular the nature of LC precursors and the factors that may drive LC differentiation. Through a systematic transcriptomic analysis of TSLP-activated dendritic cells (DCs), we unexpectedly identified markers that have been associated with a skin-homing potential as well as with a LC phenotype. We performed transcriptomic analysis of TSLP-activated blood DCs, as compared to freshly purified, Medium-, and TNF-activated DCs. Among TSLP up-regulated genes, we identified molecules associated with skin homing, LC phenotype, and LC function, as determined by a literature-based survey. Conversely, genes not expressed in LCs were not found among TSLP-induced genes. Further experiments showed that TGF-β synergized with TSLP leading to the differentiation of blood BDCA-1+ DCs into bona fide Birbeck granule-positive LCs.
2014-08-01 | GSE59237 | GEO
Project description:An Ox40-cre allele was used for lineage marking of CD4 T cells. Naive T cells that had previously expressed OX40 demonstrated a partially activated phenotype that was distinct from that of the majority of naive T cells. These results are consistent with a minor subpopulation of naive T cells being dependent on strong signaling responses to thymic self ligands. Keywords: T cell population comparison. Characterization of a novel subpopulation of naive T cells. Four types of T cells were sorted from mice (naive, CD44lo, CD44hi and Treg).
2010-04-03 | E-GEOD-13502 | biostudies-arrayexpress
Project description:Thymic stromal lymphopoietin (TSLP) is a key player in the pathogenesis of atopic diseases. Its pathophysiological relevance has sparked great interest in therapeutically targeting TSLP. Yet, so far, no small-mo lecule TSLP inhibitors exist due to the challenging nature of disrupting the protein-protein interaction between TSLP and its receptor. Here, we report the development of small-molecule TSLP receptor inhibitors using structure- based virtual screening and docking of >1,000,000 compounds followed by iterative chemical synthesis. BP79 emerged as our lead compound that effectively abrogates TSLP-triggered cytokine release at low micromolar concentrations. Topical application of BP79 yields efficient skin absorption followed by significant downregulation of atopy-relevant proinflammatory cytokines in immunocompetent skin disease models. For further analysis, we developed a human atopic disease drug discovery platform using microfluidic multi-organ chips. Here, topical application of BP79 onto atopic-like skin disease models that were co -cultivated with lung models in the presence of Th2 cells effectively suppressed immune cell infiltration and key atopy mediators including IL-13, IL-4, TSLP, and periostin, while upregulating skin barrier prote ins such as filaggrin. RNA-Seq analysis corroborated these findings and also indicated protective downstream effects on the lung epithelium. To the best of our knowledge, this represents the first report of a po tent and safe small molecule TSLPR inhibitor which has the potential to expand the therapeutic and preventive options in atopic diseases. Further, it serves as a starting point for further developments in target ing TSLP as a central player of inflammation.
2024-05-17 | GSE264457 | GEO
Project description:Atopic dermatitis (AD) is a pruritic and inflammatory disorder characterized by elevated levels of thymic stromal lymphopoietin (TSLP). Pruritus is prevalent in epidermolysis bullosa (EB). Currently, epidermal barrier disruption is known to trigger TSLP upregulation, however, mechanisms controlling TSLP expression remain incompletely understood. Tslp levels were highly upregulated in the epidermis and in the serum of keratin-deficient mice. Cultured keratinocytes either lacking keratins or expressing the dominant K14p.Arg131Pro show highly increased TSLP. Re-expression of wild-type K14 normalized TSLP levels. We demonstrate that keratins regulate Tslp expression in parts through MEK1/2 activation. The finding that 8 out of 17 EBS patients show elevated TSLP serum levels supports a major role of keratins in TSLP regulation. Our data identify a novel, keratin-dependent and cell-intrinsic regulation of Tslp. Elevated TSLP levels likely explain the high prevalence of pruritus in EBS and additional forms of EB, suggesting TSLP as novel biomarker for pruritus in EB. MEK1/2, in addition to calcineurin inhibitors, might be suitable drugs to treat itch in EB.
2016-03-26 | GSE79596 | GEO
Project description:Analysis of the gene signature of OX40+ Tregs, in comparison to OX40- Tregs and Tconvs, freshly isolated from liver cirrhosis and tumor of chronic HCV patients. Results provide insights into the metabolic mechanisms of Treg proliferation in premalignant/malignant contexts.
2018-06-26 | GSE103523 | GEO