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Retinoic acid drives intestine-specific adaptation of effector ILC2s originating from distant sites [scRNA-Seq]

ABSTRACT: Adaptation of immune cells to tissue-specific microenvironments is a crucial process in homeostasis and inflammation. Here, we show that murine effector type 2 innate lymphoid cells (ILC2s) from various organs are equally effective in repopulating ILC2 niches in other anatomical locations where they adapt tissue-specific phenotypes of target organs. Single-cell transcriptomics of ILC2 populations revealed upregulation of retinoic acid (RA) signaling in ILC2s during adaptation to the small intestinal microenvironment, and RA signaling mediated reprogramming of kidney effector ILC2s towards the small intestinal phenotype in vitro and in vivo. Inhibition of intestinal ILC2 adaptation by blocking RA signaling impaired worm expulsion during Strongyloides ratti infection, indicating functional importance of ILC2 tissue imprinting. In conclusion, this study highlights that effector ILC2s retain the ability to adapt to changing tissue-specific microenvironments, enabling them to exert tissue-specific functions, such as promoting control of intestinal helminth infections.

ORGANISM(S): Mus musculus

PROVIDER: GSE242569 | GEO | 2023/09/15

REPOSITORIES: GEO

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Retinoic acid drives intestine-specific adaptation of effector ILC2s originating from distant sites [bulk RNA-Seq]

Project description:Adaptation of immune cells to tissue-specific microenvironments is a crucial process in homeostasis and inflammation. Here, we show that murine effector type 2 innate lymphoid cells (ILC2s) from various organs are equally effective in repopulating ILC2 niches in other anatomical locations where they adapt tissue-specific phenotypes of target organs. Single-cell transcriptomics of ILC2 populations revealed upregulation of retinoic acid (RA) signaling in ILC2s during adaptation to the small intestinal microenvironment, and RA signaling mediated reprogramming of kidney effector ILC2s towards the small intestinal phenotype in vitro and in vivo. Inhibition of intestinal ILC2 adaptation by blocking RA signaling impaired worm expulsion during Strongyloides ratti infection, indicating functional importance of ILC2 tissue imprinting. In conclusion, this study highlights that effector ILC2s retain the ability to adapt to changing tissue-specific microenvironments, enabling them to exert tissue-specific functions, such as promoting control of intestinal helminth infections.

2023-09-15 | GSE242562 | GEO

In Situ Maturation and Tissue Adaptation of Type 2 Innate Lymphoid Cell Progenitors

Project description:We analyzed the full spectrum of lung ILC2s at single-cell transcriptome resolution and identified an immature population of Il18r1+ tissue-associated ILCs, that express Tcf7 and Zbtb16, transcription factors known to act in ILC progenitors, and low levels of Gata3, ST2 and ILC2 effector molecules. We revealed a continuous differentiation trajectory and validated the potential of immature Il18r1+ cells to differentiate into Gata3hi ILC2s. We found that immature ILCs were recruited into the adult lung of parabiotic and shield chimeric mice during helminth infection. Intriguingly, recruited cells generated the entire spectrum of ILC2s in the lung, consistent with their potential role in the renewal of tissue ILC2s. Our work identifies local ILC progenitors and highlights their tissue adaptation and in situ differentiation as a mechanism of ILC maintenance and phenotypic diversification

2020-10-02 | GSE141330 | GEO

Transcription factor Bcl11b controls identity and function of mature innate lymphoid cells type II

Project description:Type-2 innate lymphoid cells (ILC2s) promote anti-helminth responses and contribute to allergies. Though Bcl11b has been previously considered a T-lineage identity transcription factor (TF) that restrains the innate-cell genetic programs, we report here that Bcl11b is highly expressed in mature ILC2s and acts upstream of the key ILC2 TFs Gfi1, Gata-3, and of IL-33 receptor IL1rl1 (T1ST2). Additionally, Bcl11b-/- ILC2s de-repressed Rorγt, Ahr and IL-23 receptor, normally expressed in type-3 ILCs (ILC3s). Consequently, Bcl11b-/- ILC2s lost ILC2 functions and gained ILC3 functions, expanding in response to the protease allergen papain, however producing IL-17 and IL-22, and not IL-5 and IL-13, causing lung neutrophilia rather than eosinophilia, and diminished mucus production. Our results broaden Bcl11b's role from a T-cell only TF, and establishes that Bcl11b sustains mature ILC2 genetic and functional programs and lineage fidelity through positive regulation of essential ILC2 TFs and negative regulation of pivotal ILC3 TFs. RNA-seq analysis on sorted ILC2s from the mLNs of Bcl11bF/F Cre-ERT2 and wildtype mice at steady state following tamoxifen mediated deletion of Bcl11b

2015-07-28 | E-GEOD-67437 | biostudies-arrayexpress

Retinoid X Receptor Gamma Dictates Reactivity of Intestinal Group 2 Innate Lymphoid Cells and Constrains Type 2 Inflammation

Project description:In this work we report that retinoid x receptor gamma (Rxrg) was highly expressed in small intestinal ILC2s, but rapidly suppressed by alarming cytokines. Genetic deletion of Rxrg didn’t impact ILC2 development, but significantly facilitated ILC2 responses and type 2 inflammation induced by IL-25 or helminths. RXRγ maintained the expression of its target genes that support cholesterol efflux in ILC2s. Chemical inhibition of HMG-CoA reductase rescued the abnormal responses of RXRγ-deficient ILC2s. Furthermore, RXRγ expression in ILC2s protected the host from the intestinal mastocytosis induced by skin injury. We propose that the dynamic regulation of RXRγ expression and it mediated genomic states functions as a cell-intrinsic circuit to determine ILC2 reactivity in the small intestine.

2023-09-01 | GSE205669 | GEO

Steroid-resistant human inflammatory ILC2s are marked by CD45RO and elevated in type 2 respiratory diseases

Project description:Group 2 innate lymphoid cells (ILC2s) orchestrate protective type 2 immunity and tissue homeostatis, but have also been implicated in major human type 2 immunopathologies. However, our understanding of the mechanisms that control human ILC2 activity and phenotypic heterogeneity under inflammatory conditions remains limited. We integrated transcriptome profiling, flowcytometry characterization and functional assays to characterize human ILC2s from non-inflamed and inflamed microenvironments. We show that the transition from a resting to an activated inflammatory state in ILC2s is accompanied by a CD45RA-to-CD45RO isoform switch. CD45RA phosphatase activity suppresses ILC2 activation in resting cells, while exposure to activating cytokines induces IRF4/BATF transcription factors to promote a switch to the enzymatically restrained CD45RO isoform. Importantly, CD45RO+ ILC2 levels are increased in nasal polyps but also in the circulation of patients with chronic rhinosinusitis and asthma, which correlates with disease severity and resistance to steroid therapy. CD45RA-to-CD45RO conversion in ILC2s is sensitive to suppression by glucocorticosteroids, a mainstay therapy for patients with type-2 inflammatory disease. However, once converted, CD45RO+ ILC2s are resistant to steroids, likely via unique intrinsic metabolic reprogramming. In summary, we identify an inflammatory ILC2 subset in humans that is marked by CD45RO and is linked to severe type-2 inflammatory disease and steroid resistance.

2021-01-28 | GSE150846 | GEO

Epigenome analysis reveals novel aspects of ILC2 activation and supports a pathogenic role in asthma

Project description:Recent studies have shown that group 2 innate lymphoid cells (ILC2s) can drive eosinophilic airway inflammation in mouse models of asthma. Moreover, elevated ILC2 counts and/or activity have been reported in asthmatics, together suggesting that ILC2s play an important role in asthma pathophysiology. However, many aspects of ILC2 biology are not fully understood, including the mechanisms underlying ILC2 activation, the tissue-specific functions of ILC2s during inflammation (e.g. lung versus draining lymph node) and what drives ILC2 plasticity. Importantly, it is unknown whether human (epi)genetic variation associated with asthma susceptibility and persistence can be coupled to ILC2s. We address these questions in our manuscript by studying the epigenome of murine ILC2s obtained from Gata3-reporter mice with eosinophilic airway inflammation as well as human ILC2s obtained from peripheral blood and activated in vitro.

2018-03-14 | GSE98843 | GEO

Tissue signals imprint ILC2 identity with anticipatory function [single cell RNA-Seq]

Project description:Group 2 innate lymphoid cells (ILC2s) are distributed systemically and produce type 2 cytokines in response to a variety of stimuli, including the epithelial cytokines interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP). Transcriptional profiling of ILC2s from different tissues, however, grouped ILC2s according to their tissue of origin, even in the setting of combined IL-25, IL-33R and TSLPR-deficiency. Single-cell profiling confirmed a tissue-organizing transcriptome and identified ILC2 subsets expressing distinct activating receptors, including the major subset of skin ILC2s, which were activated preferentially by IL-18. Tissue ILC2 subsets were normal in germ- free mice, suggesting that endogenous, tissue-derived, signals drive the maturation of ILC2 subsets by controlling expression of distinct patterns of activating receptors, thus anticipating tissue-specific patterns to perturbations occurring later in life.

2018-09-10 | GSE117567 | GEO

Tissue signals imprint ILC2 identity with anticipatory function [RNA-Seq]

2018-09-10 | GSE117470 | GEO

Specification of innate type-2 lymphocytes by the transcriptional determinant Gfi1

Project description:Innate type-2 lymphoid cells (ILC2s) function in immune responses against helminth parasites and are implicated in allergic inflammation and asthma. ILC2s are activated by the epithelial-derived cytokines IL-33 and IL-25 and are major sources of the type-2 cytokines IL-5 and IL-13. We show that the transcription factor Gfi1 promotes the generation of ILC2s and controls their responsiveness during Nippostrongylus brasiliensis infection as well as IL-33- or IL-25-instigated inflammation. Gfi1 directly activates Il1rl1, which encodes the IL-33 receptor. IL- 33 signaling upregulates Gfi1, thereby constituting a positive feedback loop that enables rapid and robust expansion of ILC2s in response to IL-33 signaling. Loss of Gfi1 in activated ILC2s results in an unusual effector state involving derepression of the IL-17 inflammatory program and co-expression of IL-13 with IL-17. ChIPseq reveals key Gfi1 targeted genes that are activated or repressed to maintain ILC2 identity. We propose that Gfi1 functions as a shared determinant within innate and adaptive immune cells to specify type-2 responses, while actively repressing the IL-17 effector state. ILC2s (~3 x 10^7 cells) were sorted from the MLN of IL-25-treated mice. Chromatin fragments bound by Gfi1 were subject to ChIP using Gfi1 antibodies and followed by high-throughput sequencing.

2013-09-13 | E-GEOD-50806 | biostudies-arrayexpress

Epigenome analyses implicate ILC2s as key mediators of allergic airway inflammation

Project description:Group 2 innate lymphoid (ILC2) cells are major producers of the cytokines that drive allergic asthma and elevated levels of ILC2s have been detected in the blood and sputum of asthma patients. Asthma susceptibility has strong (epi)genetic components, but the underlying mechanisms and whether they are linked to ILC2 biology remain unclear. To reveal the molecular basis of ILC2 function in allergic airway inflammation (AAI) and assess its relevance for understanding how genetic variation affects asthma susceptibility. Gata3-IRES-YFP reporter mice were used to isolate ILC2s from bronchoalveolar lavage fluid and lymph nodes. Human naive ILC2s were purified from peripheral blood and activated in vitro. We employed RNA-Seq, ChIPm-Seq and computational approaches to study the transcriptome and epigenome in the context of ILC2 activation, tissue-specific functions and genetic susceptibility to asthma. Activated ILC2s displayed a tissue-specific gene expression signature that emerged from a highly similar epigenome. We identify superenhancers - a class of regulatory regions susceptible to epigenetic drugs - controlling ILC2 identity and asthma-associated genes. The majority of genes implicated in asthma by genome-wide association studies resided in an active or primed state in ILC2s. A substantial number of asthma-associated genetic variants were found in ILC2 gene regulatory elements. Our genome-wide analyses reveal new potential functions for ILC2s in AAI, which possess a plastic and flexible epigenome. Importantly, we reveal a strong link between gene regulatory mechanisms in ILC2s and the (epi)genetic basis of asthma susceptibility, supporting a pathogenic role for ILC2s in human asthma.

2021-05-03 | GSE90641 | GEO

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