Suppression of ILC2 differentiation from committed T cell precursors by E protein transcription factors
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA437289 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6814550.fastq.gz | Fastqsanger.gz | |||
| SRR6814560.fastq.gz | Fastqsanger.gz | |||
| SRR6814570.fastq.gz | Fastqsanger.gz | |||
| SRR6814551.fastq.gz | Fastqsanger.gz | |||
| SRR6814561.fastq.gz | Fastqsanger.gz |
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Project description:Current models propose that group 2 innate lymphoid cells are generated in the bone marrow. Here we demonstrate that subsets of these cells can differentiate from multipotent progenitors and committed T cell precursors in the thymus, both in vivo and in vitro. These thymic ILC2s can exit the thymus, circulate in the blood and home to peripheral tissues. Ablation of E protein transcription factors greatly promotes the innate lymphoid cell fate at the expense of B and T cell development. Consistently, a transcriptional network centered on the ZBTB16 transcription factor and IL-4 signaling pathway is highly up-regulated due to E protein deficiency. Our results show that ILC2 can still be generated from what are normally considered to be committed T cell precursors, and that this alternative cell fate is restrained by high levels of E protein activity in these cells.
2019-01-20 | GSE111518 | GEO
Project description:Current models propose that group 2 innate lymphoid cells (ILC2s) are generated in the bone marrow. Here, we demonstrate that subsets of these cells can differentiate from multipotent progenitors and committed T cell precursors in the thymus, both in vivo and in vitro. These thymic ILC2s exit the thymus, circulate in the blood, and home to peripheral tissues. Ablation of E protein transcription factors greatly promotes the ILC fate while impairing B and T cell development. Consistently, a transcriptional network centered on the ZBTB16 transcription factor and IL-4 signaling pathway is highly up-regulated due to E protein deficiency. Our results show that ILC2 can still arise from what are normally considered to be committed T cell precursors, and that this alternative cell fate is restrained by high levels of E protein activity in these cells. Thymus-derived lung ILC2s of E protein-deficient mice show different transcriptomes, proliferative properties, and cytokine responses from wild-type counterparts, suggesting potentially distinct functions.
| S-EPMC6446881 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below. Group 2 innate lymphoid cells (ILC2) are a subset of innate lymphocytes that produce type 2 cytokines, including IL-4, IL-5, and IL-13. GATA3 being a critical transcription factor for ILC2 development at multiple stages. However, when and how GATA3 is induced to the levels required for ILC2 development remains elusive. Herein, we identified ILC2-specific tandem GATA3-related super-enhancers (G3SE) that induce high GATA3 in ILC2-committed precursors. G3SE-deficient mice exhibit ILC2 loss in the BM, lung, liver, and small intestine, a slight ILC1 increase, and no difference in ILC3, LTi, NK cells, nor Th2 cells. Single-cell RNA-sequencing revealed that GATA3 induction in late ILC2-committed precursors depends on G3SEs and is required for the transition to mature ILC2. Cnot6l, part of the CCR4-Not deadenylase complex, is a possible GATA3 target during ILC2 development. Our findings indicate a novel regulatory mechanism for GATA3 expression during ILC2 development.
2024-05-14 | GSE218155 | GEO
Project description:Group 2 innate lymphoid cells (ILC2) are functionally poised, tissue-resident lymphocytes that respond rapidly to damage and infection at mucosal barrier sites. ILC2 reside within complex microenvironments where they are subject to cues from both the diet and invading pathogens – including helminths. Emerging evidence suggests ILC2 are acutely sensitive not only to canonical activating signals, but also perturbations in nutrient availability. In the context of helminth infection, we identify amino acid availability as a nutritional cue in regulating ILC2 responses. ILC2 were found to be uniquely pre-primed to import amino acids via the large neutral amino acid transporters Slc7a5 and Slc7a8. Cell-intrinsic deletion of these transporters individually impaired ILC2 expansion, while concurrent loss of both transporters markedly impaired the proliferative and cytokine producing capacity of ILC2. Moreover, amino acid determined the magnitude of ILC2 responses in part via tuning of mTOR. These findings implicate essential amino acids as a metabolic requisite for optimal ILC2 responses within mucosal barrier tissues.
2022-12-22 | PXD038792 | Pride
Project description:Lung-resident group 2 innate lymphoid cells (ILC2s) produce type 2 cytokines and facilitate tissue repair in response to alarmins such as IL-33 released during respiratory virus infection, but they also may be functionally suppressed by type 1 cytokines. Compared to females, males harbor significantly fewer lung ILC2s, which express notably high levels of androgen receptor (AR) compared to other lymphocytes. Here we tested the hypothesis that females and males show differential ILC2 responses upon influenza virus (IAV) infection of mice. Over the course of sublethal infection, lungs of female mice contained greater numbers of ILC2s and ILC1s compared to males. However, the female ILC2s were preferentially suppressed at the peak of infection, with a dampened type 2 program manifest as attenuated proliferation, decreased propensity to produce IL-5 and amphiregulin, and reduced expression of GATA3 and IL-33R. Naïve female ILC2s showed higher expression of IFNGR and higher phospho-STAT1 levels following stimulation by IFN, and lymphocyte-restricted STAT1 deficiency reversed suppression of female ILC2s during infection. ILC2s in naive male mice with lymphocyte-restricted AR deficiency displayed levels of IFNGR comparable to female mice, suggesting AR activity underlies sex differences in intrinsic IFNGR expression. Early life orchiectomy or lymphocyte-restricted loss of AR revealed that endogenous androgens decreased ILC2 numbers but protected males from suppression of ILC2s in IAV infection. In sum, intrinsic AR activity preserves canonical ILC2 function in males during IAV infection, which may contribute to the sex differences in morbidity secondary to IAV observed in mice and humans.
2024-12-13 | GSE190941 | GEO
Project description:Recently, circulating multi- and uni-potent human ILC precursors (ILCP) have been found in a lymphocyte population that expresses CD117 and CD127 but lacks CRTH2 and NKp44. However, these ILCPs have not been extensively characterized. We performed an unbiased Hierarchical Stochastic Neighbor Embedding (HSNE) analysis of the phenotype of peripheral blood CD117+ ILCPs which revealed the presence of three major subsets: the first expressed NKp46, the second expressed both NKp46 and CD56, while the third expressed KLRG1. Analysis of their differentiation potential on bulk and clonal levels, cytokine production and the transcriptome revealed that the NKp46+ ILCPs contain high frequencies of ILC3 precursors whereas a minority can differentiate into ILC1/NK-like cells. In contrast, KLRG1+ ILCPs are biased to the ILC2 lineage, but are highly plastic and epigenetically primed to differentiate into other ILC subsets depending on the activation signals they receive.
2019-06-05 | GSE124054 | GEO
Project description:ILC2 contribute to immune homeostasis, protective immunity and tissue repair. However, an understanding of the microenvironmental factors and transcriptional circuits that support development of these innate lymphocytes within lymphoid organs, alongside their adaptive T and B cell relatives, is only starting to emerge. Here we demonstrate that functional ILC2 arise in the embryonic thymus, from shared T cell precursors, and precede the emergence of CD4+CD8+ (double-positive) T cells. Strikingly, RORa expression repressed T cell development, whilst promoting ILC2 in the thymus. Thymic ILC2 go on to contribute to the innate type-2 response at mucosal tissues with preferential colonisation of the intestinal lamina propria. From RNAseq, ATACseq and ChIPseq data we propose a revised transcriptional circuit to explain the enigmatic co-development of T cells, ILC2 and NK cells from common progenitors in the thymus. When Notch signalling is present, Bcl11b dampens Nfil3/Id2 expression, permitting E protein-directed T cell commitment. However, concomitant expression of RORa overrides the Nfil3/Id2 repression, allowing Id2 to repress E proteins and promote ILC2 differentiation. Thus, we demonstrate that RORa expression represents a critical checkpoint at the bifurcation of the T cell and ILC2 lineages in the embryonic thymus.
2020-11-03 | GSE146743 | GEO
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: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 (ILC2) are functionally poised, tissue-resident lymphocytes that respond rapidly to damage and infection at mucosal barrier sites. ILC2 reside within complex microenvironments where they are subject to cues from both the diet and invading pathogens – including helminths. Emerging evidence suggests ILC2 are acutely sensitive not only to canonical activating signals, but also perturbations in nutrient availability. In the context of helminth infection, we identify amino acid availability as a nutritional cue in regulating ILC2 responses. ILC2 were found to be uniquely pre-primed to import amino acids via the large neutral amino acid transporters Slc7a5 and Slc7a8. Cell-intrinsic deletion of these transporters individually impaired ILC2 expansion, while concurrent loss of both transporters markedly impaired the proliferative and cytokine producing capacity of ILC2. Moreover, amino acid determined the magnitude of ILC2 responses in part via tuning of mTOR. These findings implicate essential amino acids as a metabolic requisite for optimal ILC2 responses within mucosal barrier tissues.
2022-12-22 | PXD038786 | Pride