Steroid-resistant human inflammatory ILC2s are marked by CD45RO and elevated in type 2 respiratory disease
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ABSTRACT:
PROVIDER: PRJNA638387 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11967300.fastq.gz | Fastqsanger.gz | |||
| SRR11967301.fastq.gz | Fastqsanger.gz | |||
| SRR11967302.fastq.gz | Fastqsanger.gz | |||
| SRR11967303.fastq.gz | Fastqsanger.gz | |||
| SRR11967304.fastq.gz | Fastqsanger.gz |
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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.
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Project description:Steroid-resistant human inflammatory ILC2s are marked by CD45RO and elevated in type 2 respiratory diseases
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Project description:Group 2 Innate Lymphoid Cells (ILC2s) are key players in type 2 immunity and contribute to maintaining homeostasis and responding to inflammation. ILC2s are implicated in the development of type 2 inflammation-mediated chronic disorders like asthma. While memory ILC2s have been identified in mouse, it is unknown whether human ILC2s can acquire immunological memory. Here, we demonstrate the persistence of CD45RO, a marker previously linked to inflammatory ILC2s, in resting ILC2s that have undergone prior activation. A high proportion of these cells concurrently reduce the expression of the canonical ILC marker CD127 in a tissue specific manner. Through isolation and in vitro stimulation of CD127- CD45RO+ ILC2s, we observed an augmented ability to proliferate and produce cytokines. CD127- CD45RO+ ILC2s are found in both healthy and inflamed tissues and display a gene signature of cell activation. Our findings suggest that human ILC2s can acquire innate immune memory and warrants a revision of the current strategies to identify human ILC2s.
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Project description:Transcriptome analyses of human peripheral blood ILC2, fresh after sort or after culture with activating cytokines +/- dexamethasone
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Project description:Group 2 innate lymphoid cells (ILC2s) in the lung are stimulated by inhaled allergens. ILC2s do not directly recognize allergens but they are stimulated by cytokines including interleukin (IL)-33 released by damaged epithelium.Lung ILC2s, upon stimulation, produce T helper 2 cell-type cytokines inducing T cell independent allergic lung inflammation. We now report that lung ILC2s, upon activation by an allergen or IL-33, acquire the properties of memory cells. The activated ILC2s initially proliferate and secrete cytokines, followed by a contraction phase as they stop producing cytokines. Nevertheless, some persist long after the resolution of the inflammation and acquire intrinsic capacities to react to unrelated allergens more vigorously than naïve ILC2s, thus mediating a severe allergic lung inflammation. Gene expression profiles of the previously activated ILC2s show a gene signature of memory T cells. These antigen non-specific memory ILC2s may explain why asthma patients are often sensitized to multiple allergens. ILC2s were isolated from mouse lungs from naive and IL-33 injected mice 4 days, 14 days and 4 months after the initial treatment. RNA was extracted from those ILC2 populations and analyzed for gene expression profiles. RNA was also extracted from ILC2s isolated from lung draining mediastinal lymph node (mLN) 4 days and 14 days after IL-33 treatment.
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Project description:We analyzed the total proteome of group 2 innate lymphoid cells (ILC2s) after different stimulation with interleukin-33 (IL-33), a cytokine playing a critical role in human asthma, and TL1A, a TNF-family cytokine also known to activate ILC2s. Upon combined stimulation with IL-33 plus TL1A, we show that lung ILC2s produce high amounts of IL-9 and acquire a transient ‘ILC9’ phenotype. This phenotype is characterized by simultaneous production of large amounts of type 2 cytokines (IL-5, IL-13 and IL-9), induction of the IL-2 receptor CD25 (Il2ra), and of the transcription factors IRF4, JunB and BATF, that form immune-specific complexes known to induce IL-9 expression.
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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.
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Project description:To fully characterize the heterogeneity and gene expression profile of mouse lung ILC2s, we generated RORα lineage tracer mice by crossing RoraIRES-Cre (Chou et al., 2013) and R26R-EYFP mice, which have a loxP-flanked stop sequence followed by the gene encoding yellow fluorescent protein (YFP) in the ROSA26 locus. In these RORα-YFP mice, cells expressing Rorα during their development should be irreversibly labeled by YFP. Flow cytometric analyses of lymphocytes in RORα-YFP mice showed that innate lymphoid cells type 2 (ILC2s) were marked by YFP expression. However, both adult and neonatal lung Lin−YFP+ cells were heterogeneous and included not only ILC2s (GATA-3+Thy1+) but also GATA-3−Thy1− and GATA-3lowThy1+ cells. In order to fully assess the lung ILC2 heterogeneity, we analyzed all CD45low/+Linlow cells from adult (6-week-old) and neonatal (12-day-old) RORα-YFP mouse lungs by droplet-based scRNA-seq. Unsupervised clustering of the cells revealed distinct clusters of stromal, B, T, NK cell, DC and ILC2 based on their expression of well-characterized marker genes. We then isolated the ILC2 cluster and performed a second round of unsupervised clustering to examine the existence of possible ILC2 subsets. In both adult and neonatal datasets, ILC2s were divided into subsets with each subset expressing a distinct set of ILC2-associated genes. We validated the existence of distinct ILC2 subsets in adult and neonatal lungs using flow cytometry. We also comprehensively assessed the genes that were specifically and/or differentially expressed by ILC2s compared to other immune and non-immune cell populations in our datasets. This analysis revealed the expression of well-characterized ILC2 genes such as Gata3, Rora, Areg and Il7r as well as other genes with potential immune regulatory functions.
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