Homeostatic leukotrienes, IL-25, and IL-33 signals on intestinal ILC2 status
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE144956 | GEO | 2020/02/16
REPOSITORIES: GEO
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Project description:ILC2 cells are a newly described cell type whose biology and contribution to disease are poorly understood. ILC2 cells are activated by allergens, viral infection, and/or epithelial damage via IL-33 and IL-25. ILC2 cells require IL-2, IL-7, IL-25 and IL-33 for their survival and expansion. In mice, ILC2s produce multiple mediators primarily associated with type 2 inflammation (IL-13, IL-5, IL-4, IL-6, IL-9, IL-10, GM-CSF, amphiregulin). ILC2 cells may contribute to the pathology of asthma through multiple mediators that include IL-13-independent pathways. Our goal is to compare transcriptional profiles of IL-33- or IL-25-activated ILC2 cells from blood to characterize these cells and to identify marker(s) that can be utilized to detect them in human tissue. ILC2 cells (Lineage negative, CRTH2+, CD161+, CD127+) were purified from human blood of 5 different donors by flow cytometry. The ILC2 yield ranged from 20,000 to 165,000 cells per donor (0.001-0.008% WBC). Purified ILC2s were expanded in vitro in the presence of IL-2, IL-7, IL-33 and IL-25 (each at 50 ng/ml) for 7-10 days. Expanded cells maintained the ILC2 phenotype (Lineage negative, CRTH2+, CD161+, CD127+). The cells were rested for 2 days in the presence of 1 ng/ml IL-2 and IL-7 and then treated in the presence of 1 ng/ml IL-2 and IL-7 with either media control, IL-25 (50 ng/ml), IL-33 (50 ng/ml), and/or TSLP (50 ng/ml) in combination, for 6 or 24 hours. Whole RNA was isolated via the RNeasy kit (Qiagen). Stratagene Universal Human Reference RNA was used as the reference.
2013-12-31 | E-GEOD-45458 | biostudies-arrayexpress
Project description:ILC2 cells are a newly described cell type whose biology and contribution to disease are poorly understood. ILC2 cells are activated by allergens, viral infection, and/or epithelial damage via IL-33 and IL-25. ILC2 cells require IL-2, IL-7, IL-25 and IL-33 for their survival and expansion. In mice, ILC2s produce multiple mediators primarily associated with type 2 inflammation (IL-13, IL-5, IL-4, IL-6, IL-9, IL-10, GM-CSF, amphiregulin). ILC2 cells may contribute to the pathology of asthma through multiple mediators that include IL-13-independent pathways. Our goal is to compare transcriptional profiles of IL-33- or IL-25-activated ILC2 cells from blood to characterize these cells and to identify marker(s) that can be utilized to detect them in human tissue.
2013-12-31 | GSE45458 | GEO
Project description:Homeostatic leukotrienes, IL-25, and IL-33 signals on intestinal ILC2 status
| PRJNA605441 | ENA
Project description:The ETS1 transcription factor is required for the development and cytokine-induced expansion of ILC2 ILC2 cells isolated from ETS1-deleted or litter mate control mice were cultured on OP9-DL1 with IL-7 and IL-33. Subsequently, RNA from ICOS+ cells was extracted, labelled and hybridized to Affymetrix microarrays. The goal of this study is to investigate ETS1-dependent genes in developing ILC2 cells.
2016-04-01 | E-GEOD-79742 | biostudies-arrayexpress
Project description:Group 2 innate lymphoid cells (ILC2s) orchestrate tissue homeostasis, allergic disorders and anti-helminth protective immunity through their production of cytokines. However, their rarity has hampered high-throughput genetic screening approaches to uncover novel ILC2 regulators in an unbiased manner. We combined expansion of progenitors from multi-reporter mouse strains with optimised ILC differentiation cultures to perform CRISPR-Cas9 screens for regulators of ILC2 development and function. Mef2d emerged as a critical regulator of GATA3 and IL-13, and was essential for type-2 immunity as demonstrated by conditional Mef2d-deficient mice, including a Boolean-ILC2-Cre (BIC) mouse strain developed to enable ILC2-specific gene deletion. Mechanistically, Mef2d bound and transcriptionally repressed the Zc3h12a locus encoding the endonuclease Regnase-1, a negative regulator of IL-33 receptor (ST2) and GATA3 expression, thereby promoting IL-33-mediated ILC2 proliferation and cytokine production. Notably, in ILC2s Mef2d also acted downstream of leukotriene C4-induced calcium-mediated signalling to translocate NFAT1 to the nucleus to promote type-2 gene transcription. These Mef2d-mediated pathways converge and feedback to potentiate type-2 immunity.
2024-06-28 | GSE242029 | GEO
Project description:Group 2 innate lymphoid cells (ILC2s) orchestrate tissue homeostasis, allergic disorders and anti-helminth protective immunity through their production of cytokines. However, their rarity has hampered high-throughput genetic screening approaches to uncover novel ILC2 regulators in an unbiased manner. We combined expansion of progenitors from multi-reporter mouse strains with optimised ILC differentiation cultures to perform CRISPR-Cas9 screens for regulators of ILC2 development and function. Mef2d emerged as a critical regulator of GATA3 and IL-13, and was essential for type-2 immunity as demonstrated by conditional Mef2d-deficient mice, including a Boolean-ILC2-Cre (BIC) mouse strain developed to enable ILC2-specific gene deletion. Mechanistically, Mef2d bound and transcriptionally repressed the Zc3h12a locus encoding the endonuclease Regnase-1, a negative regulator of IL-33 receptor (ST2) and GATA3 expression, thereby promoting IL-33-mediated ILC2 proliferation and cytokine production. Notably, in ILC2s Mef2d also acted downstream of leukotriene C4-induced calcium-mediated signalling to translocate NFAT1 to the nucleus to promote type-2 gene transcription. These Mef2d-mediated pathways converge and feedback to potentiate type-2 immunity.
2024-07-03 | GSE262028 | GEO
Project description:Group 2 innate lymphoid cells (ILC2s) orchestrate tissue homeostasis, allergic disorders and anti-helminth protective immunity through their production of cytokines. However, their rarity has hampered high-throughput genetic screening approaches to uncover novel ILC2 regulators in an unbiased manner. We combined expansion of progenitors from multi-reporter mouse strains with optimised ILC differentiation cultures to perform CRISPR-Cas9 screens for regulators of ILC2 development and function. Mef2d emerged as a critical regulator of GATA3 and IL-13, and was essential for type-2 immunity as demonstrated by conditional Mef2d-deficient mice, including a Boolean-ILC2-Cre (BIC) mouse strain developed to enable ILC2-specific gene deletion. Mechanistically, Mef2d bound and transcriptionally repressed the Zc3h12a locus encoding the endonuclease Regnase-1, a negative regulator of IL-33 receptor (ST2) and GATA3 expression, thereby promoting IL-33-mediated ILC2 proliferation and cytokine production. Notably, in ILC2s Mef2d also acted downstream of leukotriene C4-induced calcium-mediated signalling to translocate NFAT1 to the nucleus to promote type-2 gene transcription. These Mef2d-mediated pathways converge and feedback to potentiate type-2 immunity.
2024-07-03 | GSE242030 | GEO
Project description:Group 2 innate lymphoid cells (ILC2s) orchestrate tissue homeostasis, allergic disorders and anti-helminth protective immunity through their production of cytokines. However, their rarity has hampered high-throughput genetic screening approaches to uncover novel ILC2 regulators in an unbiased manner. We combined expansion of progenitors from multi-reporter mouse strains with optimised ILC differentiation cultures to perform CRISPR-Cas9 screens for regulators of ILC2 development and function. Mef2d emerged as a critical regulator of GATA3 and IL-13, and was essential for type-2 immunity as demonstrated by conditional Mef2d-deficient mice, including a Boolean-ILC2-Cre (BIC) mouse strain developed to enable ILC2-specific gene deletion. Mechanistically, Mef2d bound and transcriptionally repressed the Zc3h12a locus encoding the endonuclease Regnase-1, a negative regulator of IL-33 receptor (ST2) and GATA3 expression, thereby promoting IL-33-mediated ILC2 proliferation and cytokine production. Notably, in ILC2s Mef2d also acted downstream of leukotriene C4-induced calcium-mediated signalling to translocate NFAT1 to the nucleus to promote type-2 gene transcription. These Mef2d-mediated pathways converge and feedback to potentiate type-2 immunity.
2024-07-03 | GSE242146 | GEO
Project description:Background: Chronic rhinosinusitis with nasal polyposis (CRSwNP) in western countries is characterized by eosinophilia, IgE production and Th2 cytokine expression. Type 2 innate lymphoid cells (ILC2) from polyps produce IL-5 and IL-13 in response to IL-25 and IL-33 although the relevance of this axis to local mucosal T cell responses is unknown. Objective: To investigate the role of the IL-25/IL-33 axis in local mucosal T cell responses in CRSwNP. Methods: Polyp tissue and blood were obtained from patients undergoing nasal polypectomy. Control nasal biopsies and blood were obtained from healthy volunteers. Tissue was cultured in a short-term explant model. T cell surface phenotype/intracellular cytokines were assessed by flow cytometry. TCR Vβ analysis was performed with the immunoSEQ assay. Microarrays were performed for gene expression analysis. Results: Using nasal polyp tissue, numerous IL-25 receptor (IL-17RB) positive polarized Th2 cells were identified which were absent in the healthy nasal mucosa and periphery. IL-17RB+CD4+ polyp Th2 cells co-expressed ST2 (IL-33 receptor) and responded to IL-25 and IL-33 with enhanced IL-5 and IL-13 production. Within IL-17RB+CD4+ T cells several identical TCR Vβ CDR3 sequences were identified in different subjects suggesting clonal expansion driven by a common antigen. Abundant IL-17 producing T cells were observed in healthy nasal mucosal and polyp populations with Th17-related genes the most overexpressed compared to peripheral blood T cells. Conclusion: IL-25 and IL-33 may interact locally with IL-17RB+ST2+ polyp T cells to augment Th2 responses in CRSwNP. A local Th17 response may be the default signature in healthy nasal mucosal immune homeostasis. Three biological replicates. T-helper cells were isolated nasal polyps by explant culture from patients with chronic rhinosinusitis. Cells were then sorted based upon expression of IL17RB by flow cytometric sorting. Resting and activated IL-17RB+ve cells were compared with resting and activated IL-17RB-ve cells.
2015-12-22 | E-GEOD-70898 | biostudies-arrayexpress
Project description:Interleukin-25 and group 2 innate lymphoid cells (ILC2s) defend the host against intestinal helminth infection, and are associated with inappropriate allergic reactions. Recently, it was reported that IL-33-activated ILC2s augment protective tissue-specific pancreatic cancer immunity. Here we show a diametrically opposite role for intestinal IL-25-activated ILC2s where they create an innate cancer-permissive microenvironment. Colorectal cancer (CRC) patients with higher tumor IL25 expression have reduced survival, and increased IL-25 Rexpressing tumor-resident ILC2s and myeloid-derived suppressor cells (MDSCs) associated with impaired anti-tumor responses. Ablation of IL-25-signalling reduced tumors, virtually doubling life-expectancy in an Apc-mutation-driven model of spontaneous intestinal tumorigenesis. Mechanistically, IL-25 promotes tumor ILC2s, which sustain MDSCs to suppress anti-tumor immunity. Therapeutic blockade of IL-25-signalling decreased ILC2s, MDSCs and adenoma/adenocarcinoma, while increasing anti-tumor IFNg and adaptive T cell immunity. Thus, the roles of innate epithelium-derived cytokines IL-25 and IL-33, and ILC2s in cancer cannot be generalized, and instead offer differential pathways for therapeutic intervention.
2022-04-20 | GSE199113 | GEO