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Identification of N6-methyladenosine (m6A) modified RNA in ILC2 of WT and Mettl3 Klrg1Cre mice

ABSTRACT: Innate lymphoid cells (ILCs) are able to directly respond to alarmin signals and produce an array of effector molecules for immune protection and tissue homeostasis. However, how posttranscriptional machinery in ILCs execute extracellular stimuli towards robust gene expression is yet to understand. Here, we reported a cell type-specific role of N6-methyladenosine (m6A) RNA methylation in ILCs. Inducible deletion of m6A methyltransferase METTL3 had little impact on ILC maintenance in the steady state or cytokine-induced ILC1 or ILC3 activation, but dramatically diminished IL-25-triggered ILC2 response. Specific deletion of Mettl3 in ILC2 significantly attenuated cell expansion, cytokine production, inter-organ migration, and anti-helminth immunity. To investigate the molecular mechanism by which m6A modification regulates ILC2 response, we subjected ILC2 of WT and Mettl3 Klrg1Cre mice to a m6A-tagged mRNA immunoprecipitation sequencing (meRIP-seq) to identify the m6A modified mRNA.

ORGANISM(S): Mus musculus

PROVIDER: GSE223082 | GEO | 2023/06/26

REPOSITORIES: GEO

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Identification of N6-methyladenosine (m6A) modified RNA in activated ILC2

Project description:Innate lymphoid cells (ILCs) are able to directly respond to alarmin signals and produce an array of effector molecules for immune protection and tissue homeostasis. However, how posttranscriptional machinery in ILCs execute extracellular stimuli towards robust gene expression is yet to understand. Here, we reported a cell type-specific role of N6-methyladenosine (m6A) RNA methylation in ILCs. Inducible deletion of m6A methyltransferase METTL3 had little impact on ILC maintenance in the steady state or cytokine-induced ILC1 or ILC3 activation, but dramatically diminished IL-25-triggered ILC2 response. Specific deletion of Mettl3 in ILC2 significantly attenuated cell expansion, cytokine production, inter-organ migration, and anti-helminth immunity. To investigate the molecular mechanism by which m6A modification regulates ILC2 response, we subjected IL-25-activated iILC2 to a m6A-tagged mRNA immunoprecipitation sequencing (meRIP-seq) to identify the m6A modified mRNA.

2023-06-26 | GSE207292 | GEO

Identification of N6-methyladenosine (m6A) modified RNA in activated ILC1

Project description:Innate lymphoid cells (ILCs) are able to directly respond to alarmin signals and produce an array of effector molecules for immune protection and tissue homeostasis. However, how posttranscriptional machinery in ILCs execute extracellular stimuli towards robust gene expression is yet to understand. Here, we reported a cell type-specific role of N6-methyladenosine (m6A) RNA methylation in ILCs. Inducible deletion of m6A methyltransferase METTL3 had little impact on ILC maintenance in the steady state or cytokine-induced ILC1 or ILC3 activation, but dramatically diminished IL-25-triggered ILC2 response. Specific deletion of Mettl3 in ILC2 significantly attenuated cell expansion, cytokine production, inter-organ migration, and anti-helminth immunity. To investigate the molecular mechanism by which m6A modification regulates ILC response, we subjected IL-12 plus IL-18-activated ILC1 to a m6A-tagged mRNA immunoprecipitation sequencing (meRIP-seq) to identify the m6A modified mRNA.

2023-06-26 | GSE223081 | GEO

Identification of N6-methyladenosine (m6A) modified RNA in activated ILC3

Project description:Innate lymphoid cells (ILCs) are able to directly respond to alarmin signals and produce an array of effector molecules for immune protection and tissue homeostasis. However, how posttranscriptional machinery in ILCs execute extracellular stimuli towards robust gene expression is yet to understand. Here, we reported a cell type-specific role of N6-methyladenosine (m6A) RNA methylation in ILCs. Inducible deletion of m6A methyltransferase METTL3 had little impact on ILC maintenance in the steady state or cytokine-induced ILC1 or ILC3 activation, but dramatically diminished IL-25-triggered ILC2 response. Specific deletion of Mettl3 in ILC2 significantly attenuated cell expansion, cytokine production, inter-organ migration, and anti-helminth immunity. To investigate the molecular mechanism by which m6A modification regulates ILC response, we subjected IL-1 plus IL-23-activated ILC3 to a m6A-tagged mRNA immunoprecipitation sequencing (meRIP-seq) to identify the m6A modified mRNA.

2023-06-26 | GSE223083 | GEO

Comprehensive protein-expression map of ILC2 and ILC3 subsets in healthy human skin

Project description:Innate lymphoid cells (ILCs) have emerged as essential players in the skin-associated immune system in health and inflammatory skin diseases. Their low numbers and lack of specific markers hampered extensive characterization and consequently resulted in limited knowledge of their protein expression. Here, we combined flow cytometry and state-of-the-art proteomics to comprehensively describe the proteins constitutively expressed by ILC2 and ILC3 subsets derived from healthy human skin and peripheral blood. We quantified 6666 proteins from skin ILC and identified 608 differentially expressed proteins in the investigated subsets. In addition to the current analyses, highlighting new functions of ILC, the ILC proteomic libraries and the proteomes of the ILC2 and ILC3 subsets will serve as valuable resources for future analyses of ILC function and are available at http://skin.science.

2023-10-10 | PXD037817 | Pride

Gene expression analysis of CD4+ and CD4- ILC1 subsets by RNAseq

Project description:Innate lymphoid cell (ILC) subsets that mirror helper T cells in their effector cytokine profiles have recently emerged as central players in both homeostatic and inflammatory conditions. Like their Th1, Th2 and Th17/Th22 helper T cell counterparts, ILC subsets are categorized based on their expression of specific transcription factors and effector cytokines: group 1 ILC (ILC1) express T-bet and IFN-Î³; group 2 ILC (ILC2) express GATA-3 and type 2 effector cytokines such as IL-13 and IL-5; and group 3 ILC (ILC3) express RORgt and the cytokines IL-22 and/or IL-17. Under this nomenclature, natural killer (NK) cells and lymphoid tissue inducers (LTi) are considered ILC1 and ILC3, respectively. ILC1 contain both CD4+ and CD4- populations, but whether this phenotypic characteristic reflects functional differences between these two populations is unknown. These studies examine the gene expression profiles of CD4+ vs CD4- ILC1 in a cohort of healthy control subjects. ILC subsets were isolated from the peripheral blood of healthy control subjects. cDNA was isolated and amplified from sorted populations, and gene expression was analyzed by RNAseq

2015-12-31 | E-GEOD-69596 | biostudies-arrayexpress

Characterization of rat ILCs reveals ILC2 as the dominant intestinal subset

Project description:Innate lymphoid cells (ILCs) are tissue-resident lymphocytes that lack antigen-specific receptors and exhibit innate effector functions such as cytokine production that play an important role in immediate responses to pathogens especially at mucosal sites. Mouse and human ILC subsets have been extensively characterized in various tissues and in blood. In this study, we present the first characterization of ILCs and ILC subsets in rat gut and secondary lymphoid organs. ScRNAseq and flow cytometric data shows that phenotype and function of rat ILC subsets are conserved similar to human and mouse ILCs. However, contrary to human and mouse, our study unexpectedly revealed that ILC2 and not ILC3 was by far the dominant ILC subset in the rat intestinal lamina propria. ILC2 predominance in the gut was independent of rat strain, sex or housing facility. In contrast, ILC3 were the main ILC subset in mesenteric lymph nodes and Peyer patches, in which strain-dependent differences in ILC frequencies were also observed. In conclusion, our study demonstrates that in spite of highly conserved phenotype and function between mice, rat and humans, the distribution of ILC subsets in the intestinal mucosa is species-dependent, likely in response to both genetic and environmental factors.

2020-02-12 | GSE143920 | GEO

Amino acid availability acts as a metabolic rheostat to determine the magnitude of ILC2 responses - WT ILC2

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

Skin-resident innate lymphoid cells converge on a pathogenic effector state

Project description:Tissue-resident innate lymphoid cells (ILCs) help sustain barrier function and respond to local signals. ILCs are traditionally classified as ILC1, ILC2 or ILC3 on the basis of their expression of specific transcription factors and cytokines1. In the skin, disease-specific production of ILC3-associated cytokines interleukin (IL)-17 and IL-22 in response to IL-23 signalling contributes to dermal inflammation in psoriasis. However, it is not known whether this response is initiated by pre-committed ILCs or by cell-state transitions. Here we show that the induction of psoriasis in mice by IL-23 or imiquimod reconfigures a spectrum of skin ILCs, which converge on a pathogenic ILC3-like state. Tissue-resident ILCs were necessary and sufficient, in the absence of circulatory ILCs, to drive pathology. Single-cell RNA-sequencing (scRNA-seq) profiles of skin ILCs along a time course of psoriatic inflammation formed a dense transcriptional continuum—even at steady state—reflecting fluid ILC states, including a naive or quiescent-like state and an ILC2 effector state. Upon disease induction, the continuum shifted rapidly to span a mixed, ILC3-like subset also expressing cytokines characteristic of ILC2s, which we inferred as arising through multiple trajectories. We confirmed the transition potential of quiescent-like and ILC2 states using in vitro experiments, single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq) and in vivo fate mapping. Our results highlight the range and flexibility of skin ILC responses, suggesting that immune activities primed in healthy tissues dynamically adapt to provocations and, left unchecked, drive pathological remodelling.

2020-12-14 | GSE149622 | GEO

Identification and characterization of regenerative innate lymphoid cells from pluripotent stem cells [WT_ILC/R9_iILC_SmartSeq2]

Project description:We identified that synergistic and inducible expression of Runx1 and Hoxa9 in pluripotent stem cells gave rise to engraftable iHPC capable of developing into mature ILCs in the Rag2-/-Il2rg-/- recipients. We performed single-cell RNA-seq on the entire regenerative CD45.2+GFP+Lin-CD127+ R9-ILC population from the intestine of Rag2-/-Il2rg-/- recipient mice and the CD45.2+Lin-CD127+ WT-ILC population from the intestine of wild type mice (C57BL/6, CD45.2). Single-cell transcriptome illustrated the transcriptome landscape of the R9-ILCs and wild type ILCs including ILC1, ILC2 and ILC3.

2022-09-30 | GSE186777 | GEO

The Tumor Microenvironment Shapes Innate Lymphoid Cells in Patients with Hepatocellular Carcinoma

Project description:Objective: Hepatocellular carcinoma (HCC) represents a typical inflammation-associated cancer. Tissue resident innate lymphoid cells (ILCs) have been suggested to control tumor surveillance. Here we studied how the local cytokine milieu controls ILCs in HCC. Design: We performed bulk RNA sequencing of HCC tissue as well as flow cytometry and single-cell RNA sequencing of enriched ILCs from non-tumor liver, margin and tumor core derived from 48 HCC patients. Simultaneous measurement of protein and RNA expression at the single-cell level (AbSeq) identified precise signatures of ILC subgroups. In-vitro culturing of ILCs was used to validate findings from in-silico analysis. Analysis of RNA-sequencing data from large HCC cohorts allowed stratification and survival analysis based on transcriptomic signatures. Results: RNA sequencing of tumor, non-tumor and margin identified tumor-dependent gradients of which were not only associated with poor survival but also control ILC plasticity. Single-cell RNA sequencing and flow cytometry of ILCs from HCC livers identified NK-like cells in the non-tumor tissue, losing their cytotoxic profile as they transitioned into tumor ILC1 and NK-like-ILC3 cells. Tumor ILC composition was mediated by cytokine gradients that directed ILC plasticity towards activated tumor ILC2s. This was liver-specific and not seen in ILCs from PBMC. Patients with high ILC2/ILC1 ratio expressed IL-33 in the tumor that promoted ILC2 generation which was associated with better survival. Conclusion: Our results suggest that the tumor cytokine milieu controls ILC composition and HCC outcome. Specific changes of cytokines modify ILC composition in the tumor by inducing plasticity and alter ILC function.

2021-08-11 | GSE179746 | GEO

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