A novel model to study deficiency of RORγt+ Tregs reveals net suppressive function and dependency on the CCR6/CCL20 axis for expansion and activation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA744926 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15075455.fastq.gz | Fastqsanger.gz | |||
| SRR15075456.fastq.gz | Fastqsanger.gz | |||
| SRR15075457.fastq.gz | Fastqsanger.gz | |||
| SRR15075458.fastq.gz | Fastqsanger.gz | |||
| SRR15075459.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 6 |
Similar Datasets
Project description:Background: Recently, Tregs expressing the Th17 characteristic transcription factor RORγt were identified (biTregs). Both, pro- and anti-inflammatory functions have been described and the sum effect of biTreg deficiency in inflammation remains unknown. Furthermore, it is unclear, whether biTregs are specialized for the control of a defined type of immune response, as in particular Th2 or Th17 immunity. Methods: FACsorted CD4+ T-cells from fluorescence reporter mice, containing or lacking biTregs, were transferred into RAG1-/- recipients and the nephrotoxic nephritis model of glomerulonephritis was studied. Interactions of biTregs with various leukocyte populations were assessed by multicolor immunofluorescence. Furthermore, biTregs were compared to other Treg subtypes including suppression assays and RNAseq analyses. Finally, the role of the CCR6/CCL20 axis for biTreg biology was characterized. Results: Lack of endogenous biTregs resulted in aggravation of glomerulonephritis, demonstrating net immunosuppressive functions. However, contrary to our hypothesis, biTreg deficiency did not result in selectively overshooting Th2 or Th17 responses. Comprehensive analysis instead revealed a unique functional and transcriptional biTreg profile, including high production of IL-10 and dependency on IL-6R, cMAF and IKZF3 activation. Interestingly, we found that expression of the chemokine receptor CCR6 marked a particularly activated biTreg subset, whose absence significantly worsened glomerulonephritis. Unexpectedly, we found that signaling via the CCR6/CCL20 axis mediates biTreg expansion, rather than trafficking. Our data indicate net immunosuppressive effects of endogenous biTregs, with no preference for regulation of Th2 or Th17 responses. Surprisingly, signaling via the Conclusion: CCR6/CCL20 axis was integral for biTreg expansion and activation, which offers novel therapeutic options.
2024-07-01 | GSE179771 | GEO
Project description:We identified transcriptional changes in Tregs in response to IL18 stimulation, including upregulation of CCR6
2020-07-27 | GSE153153 | GEO
Project description:IL18 signaling controls the CCR6-CCL20-dependent migration axis used by IL18R+ Tregs to enter the thymus
| PRJNA641640 | ENA
Project description:The experiment was designed to compare transcriptomic differences between WT and Ccr6 KO Tregs during activation. WT and Ccr6 KO Tregs, cells were isolated from mice and cultured in vitro for 3 days with activation using anti-CD3/CD28 beads. Total RNA was extracted using the Trizol method. Quantity and quality were assessed using a Thermo Scientific™ NanoDrop™ 2000/2000c Spectrophotometer. Novogene Corporation Inc prepared the RNA-seq 250-300 bp insert cDNA library. Illumina HiSeq platform PE150 sequencing was used for sequencing, yielding 20M raw reads/sample. Mus Musculus mm39 was used as the reference genome for alignment.
2024-08-10 | E-MTAB-14288 | biostudies-arrayexpress
Project description:Background: The cancer-related mortality of primary liver cancer ranks third globally, and hepatocellular carcinoma (HCC) is predominant, posing a serious threat to patients' health. Understanding HCC's pathogenesis and target molecules is crucial for early diagnosis and prognosis. Extracellular vesicles (EVs) and their carried miRNAs impact tumor progression. This study aims to investigate miR-183-5p in HCC cell-derived EVs on angiogenesis, progression, and metastasis, and provide diagnostic and therapeutic evidence. Methods: q-PCR was used to evaluate the expression of miR-183-5p in HCC tissue and plasma EV samples. Contrast-enhanced ultrasound and The Cancer Genome Atlas evaluated its correlation with angiogenesis and prognosis. In vitro, cell counting kit-8 (CCK-8), colony formation, transwell, tube formation, and permeability assays examined the effect of HCC cell-derived EVs on human umbilical vein endothelial cells (HUVECs). Subcutaneous tumor and lung metastasis models in nude mice verified it in vivo effects. RNA sequencing and databases predicted downstream genes and pathways, and dual luciferase and western blotting assays verified binding and activation. Conditioned medium from treated HUVECs was used on HCC cells, and chemokine levels measured. The CCL20/CCR6 axis effect was studied in vitro and in vivo by knocking down CCR6. Results: This study revealed the abnormal upregulation of miR-183-5p in both tissues and plasma EVs from patients with HCC, and its association with unfavorable prognosis. In vivo experiments, the promoting effects of miR-183-5p in HCC cell-derived EVs on the progression, metastasis and angiogenesis were verified by employing subcutaneous tumor formation models and lung metastasis models in nude mice. We demonstrated that miR-183-5p in HCC cell-derived EVs induced HUVECs proliferation, migration, angiogenesis and permeability by downregulating SIK1 expression and activating the PI3K/AKT signaling pathway in vitro. Moreover, stimulated HUVECs could secrete the chemokine CCL20 and induce HCC progression and metastasis through the CCL20/CCR6 signal pathway in vitro and in vivo. Conclusion: The findings indicated that miR-183-5p delivered by EVs from HCC cells is crucial in mediating the communication between HUVECs and HCC cells by modulating the SIK1/PI3K/AKT and CCL20/CCR6 signaling pathways, and EVs-miR-183-5p might be a potential therapeutic target for HCC patients.
2025-03-25 | GSE289187 | GEO
Project description:Drosophila melanogaster net, net, is differentially expressed in 18 experiment(s);
| FBgn0002931 | ExpressionAtlas
Project description:Drosophila melanogaster net, net, is expressed in 3 baseline experiment(s);
| FBgn0002931 | ExpressionAtlas
Project description:Bulk RNA-seq of Tregs from WT mice and Ccr6 KO mice
| PRJEB78374 | ENA
Project description:Invariant natural killer T cells (iNKT) expressing the retinoic acid receptor-related orphan receptor γt (RORγt) and producing IL-17 represent a minor subset of CD1d-restricted iNKT cells (iNKT17) in C57BL/6J (B6) mice. We aimed in this study to define the reasons for their low distribution and the sequence of events accompanying their normal thymic development. We found that RORγt+ iNKT cells have higher proliferation potential and a greater propensity to apoptosis than RORγt- iNKT cells. These cells do not likely reside in the thymus indicating that thymus emigration, and higher apoptosis potential, could contribute to RORγt+ iNKT cell reduced thymic distribution. Ontogeny studies suggest that mature HSAlow RORγt+ iNKT cells might develop through developmental stages defined by a differential expression of CCR6 and CD138 during which RORγt expression and IL-17 production capabilities are progressively acquired. Finally, we found that RORγt+ iNKT cells perceive a strong TCR signal that could contribute to their entry into a specific Th17 like developmental program influencing their survival and migration. Overall, our study proposes a hypothetical thymic developmental sequence for iNKT17 cells, which could be of great use to study molecular mechanisms regulating this developmental program.
2019-10-19 | GSE139084 | GEO
Project description:Background and Purpose: The chemokine receptor CCR6 is important in guiding pathogenic T17 cells that are implicated in numerous autoimmune diseases including psoriasis to sites of inflammation via the chemokine CCL20. On this basis, pharmacological interventions that inhibit CCR6+ immune cell migration provide a novel therapeutic approach for such diseases. However, the translatability from pre-clinical models to human diseases of such an intervention has so far not been assessed in detail. Here, we evaluate the translatability of a preclinical model of Aldara induced skin inflammation to psoriasis with a particular focus on immune cell trafficking and assess the efficacy of the novel, orally available CCR6 antagonist IDOR-1117-2520 in this model. Experimental Approach: Here, we evaluated the in vivo therapeutic effects of IDOR-1117-2520, a novel, highly selective, potent, and orally available CCR6 small molecule inhibitor, in the Aldara mouse model of skin inflammation. To understand in detail CCR6 inhibition on the inflammatory response, flow cytometry, RNA sequencing, and transcriptome-based cell type deconvolution approaches were used to characterize immune cell migration patterns and to compare the results to publicly available human psoriasis transcriptomics data. Key Results: IDOR-1117-2520 dose dependently reduced infiltration of CCR6 + immune cells into inflamed skin and was equally efficacious as IL-17 and IL-23 inhibition in reducing inflammation in the skin. Pathway analysis highlighted the strong molecular similarities in immune response between human psoriasis and the Aldara mouse model. Genes associated with the IL-17/IL-23 pathway were prominently expressed in both human psoriasis and in the mouse model. CCR6 inhibition modulated multiple pathways associated with inflammation beyond the proximal IL-17/IL-23 pathway. A chemokine-chemokine receptor interaction map implicated the CCL20-CCR6 as the dominant axis in recruiting pathogenic T17 cells in this model system, as well as in human psoriasis. Conclusion and Implications: These results suggest that IDOR-1117-2520 could provide a promising novel targeted therapeutic approach to treating psoriasis and, potentially, other autoimmune diseases with an involvement of CCR6/CCL20 axis and the IL-17/IL-23 pathway. The data provide rationale for the further development of IDOR-1117-2520, which is currently being evaluated in a clinical phase 1 trial (ISRCTN28892128).
2025-04-01 | GSE289485 | GEO