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The molecular and epigenetic mechanisms of innate lymphoid cell (ILC) memory and its relevance for asthma.

ABSTRACT: Repetitive exposure of Rag1-/- mice to the Alternaria allergen extract generated a form of memory that elicited an asthma-like response upon a subthreshold recall challenge 3-15 wk later. This memory was associated with lung ICOS+ST2+ ILC2s. Genetic, pharmacologic, and antibody-mediated inhibition and adoptive transfer established an essential role for ILC2s in memory-driven asthma. ATAC-seq demonstrated a distinct epigenetic landscape of memory ILC2s and identified Bach2 and AP1 (JunD and Fosl2) motifs as major drivers of altered gene accessibility. scRNA-seq, gene knockout, and signaling studies suggest that repetitive allergenic stress induces a gene repression program involving Nr4a2, Zeb1, Bach2, and JunD and a preparedness program involving Fhl2, FosB, Stat6, Srebf2, and MPP7 in memory ILC2s. A mutually regulated balance between these two programs establishes and maintains memory. The preparedness program (e.g., Fhl2) can be activated with a subthreshold cognate stimulation, which down-regulates repressors and activates effector pathways to elicit the memory-driven phenotype.

SUBMITTER: Verma M

PROVIDER: S-EPMC8176441 | biostudies-literature |

REPOSITORIES: biostudies-literature

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The Molecular and Epigenetic Mechanisms of Innate Lymphoid Cell (ILC) Memory and its Relevance for Asthma

Project description:Repetitive exposure of Rag1-/- mice to the Alternaria allergen extract generated a form of memory that elicited an asthma-like response upon a subthreshold recall challenge 3-15 weeks later. This memory was associated with lung ICOS+ST2+ILC2s. Genetic, pharmacologic and antibody-mediated inhibition, and adoptive transfer established an essential role for ILC2s in memory-driven asthma. ATAC-seq demonstrated a distinct epigenetic landscape of memory ILC2s, and identified Bach2 and AP1 (JunD and Fosl2) motifs as major drivers of altered gene accessibility. scRNA-seq, gene knockout and signaling studies suggest that repetitive allergenic stress induces a gene repression program involving Nr4a2, Zeb1, Bach2, and JunD, and a preparedness program involving Fhl2, FosB, Stat6, Srebf2 and MPP7 in memory ILC2s. A mutually regulated balance between these two programs establishes and maintains memory. The preparedness program (e.g. Fhl2) can be activated with a subthreshold cognate stimulation, which downregulates repressors and activates effector pathways to elicit the memory-driven phenotype.

2021-05-31 | GSE172258 | GEO

The Molecular and Epigenetic Mechanisms of Innate Lymphoid Cell (ILC) Memory and its Relevance for Asthma

Project description:The Molecular and Epigenetic Mechanisms of Innate Lymphoid Cell (ILC) Memory and its Relevance for Asthma

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Innate lymphoid cell memory.

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Project description:Using multiparameter flow cytometry human innate lymphoid cell (ILC) subsets can be detected in the circulation, in relatively low frequencies. Despite the low frequency of ILCs in circulation, ex vivo experiments have demonstrated that these ILCs release extremely large per cell quantities of signature ILC cytokines following activation. To determine how activated ILC cytokine production is regulated, ILC subsets were activated in the presence or absence of the immunoregulatory cytokines IL-10 and TGF-?. An examination of circulating ILC subsets revealed surface expression of IL-10R? and mRNA expression of both IL-10R? and TGF-?R1 for all ILC subsets. Stimulated ILC1 production of IFN-? was decreased by TGF-? and not IL-10. Interestingly, ILC2s stimulated in the presence of IL-10 had a marked reduction in cytokine production of IL-5 and IL-13 while TGF-? had no effect on ILC2 cytokine production. Ex vivo activated ILC1 and ILC2 subsets were also found to be a source of the immunoregulatory cytokine IL-10, raising the potential for ILC-mediated regulation of immune cells. These findings demonstrate the differential effects of immunoregulatory cytokines IL-10 and TGF-? on activated ILC1 and ILC2 populations ex vivo.

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Human innate lymphoid cell precursors express CD48 that modulates ILC differentiation through 2B4 signaling.

Project description:Innate lymphoid cells (ILCs) develop from common lymphoid progenitors (CLPs), which further differentiate into the common ILC progenitor (CILP) that can give rise to both ILCs and natural killer (NK) cells. Murine ILC intermediates have recently been characterized, but the human counterparts and their developmental trajectories have not yet been identified, largely due to the lack of homologous surface receptors in both organisms. Here, we show that human CILPs (CD34+CD117+α4β7+Lin-) acquire CD48 and CD52, which define NK progenitors (NKPs) and ILC precursors (ILCPs). Two distinct NK cell subsets were generated in vitro from CD34+CD117+α4β7+Lin-CD48-CD52+ and CD34+CD117+α4β7+Lin-CD48+CD52+ NKPs, respectively. Independent of NKPs, ILCPs exist in the CD34+CD117+α4β7+Lin-CD48+CD52+ subset and give rise to ILC1s, ILC2s, and NCR+ ILC3s, whereas CD34+CD117+α4β7+Lin-CD48+CD52- ILCPs give rise to a distinct subset of ILC3s that have lymphoid tissue inducer (LTi)-like properties. In addition, CD48-expressing CD34+CD117+α4β7+Lin- precursors give rise to tissue-associated ILCs in vivo. We also observed that the interaction of 2B4 with CD48 induced differentiation of ILC2s, and together, these findings show that expression of CD48 by human ILCPs modulates ILC differentiation.

| S-EPMC8294935 | biostudies-literature

CD4+ Group 1 Innate Lymphoid Cells (ILC) Form a Functionally Distinct ILC Subset That Is Increased in Systemic Sclerosis.

Project description:Innate lymphoid cells (ILC) are a heterogeneous group of cellular subsets that produce large amounts of T cell-associated cytokines in response to innate stimulation in the absence of Ag. In this study, we define distinct patterns of surface marker and cytokine expression among the ILC subsets that may further delineate their migration and function. Most notably, we found that the subset previously defined as group 1 ILC (ILC1) contains CD4(+) CD8(-), CD4(-) CD8(+), and CD4(-) CD8(-) populations. Although all ILC1 subsets shared characteristics with Th1 cells, CD4(+) ILC1 also demonstrated significant phenotypic and functional heterogeneity. We also show that the frequencies of CD4(+) ILC1 and NKp44(+) group 3 ILC, but not CD4(-) ILC1 or group 2 ILC, are increased in the peripheral blood of individuals with systemic sclerosis (SSc), a disease characterized by fibrotic and vascular pathology, as well as immune dysregulation. Furthermore, we demonstrate that CD4(+) and CD4(-) ILC1 are functionally divergent based on their IL-6Rα expression and that the frequency of IL-6Rα expression on ILC is altered in SSc. The distinct phenotypic and functional features of CD4(+) and CD4(-) ILC1 suggest that they may have differing roles in the pathogenesis of immune-mediated diseases, such as SSc.

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Project description:Although cigarette smoking is known to exacerbate asthma, only a few clinical asthma studies have been conducted involving smokers. Here we show, by comparing paired sputum and blood samples from smoking and non-smoking patients with asthma, that smoking associates with significantly higher frequencies of pro-inflammatory, natural-cytotoxicity-receptor-non-expressing type 3 innate lymphoid cells (ILC3) in the sputum and memory-like, CD45RO-expressing ILC3s in the blood. These ILC3 frequencies positively correlate with circulating neutrophil counts and M1 alveolar macrophage frequencies, which are known to increase in uncontrolled severe asthma, yet do not correlate with circulating eosinophil frequencies that characterize allergic asthma. In vitro exposure of ILCs to cigarette smoke extract induces expression of the memory marker CD45RO in ILC3s. Cigarette smoke extract also impairs the barrier function of airway epithelial cells and increases their production of IL-1β, which is a known activating factor for ILC3s. Thus, our study suggests that cigarette smoking increases local and circulating frequencies of activated ILC3 cells, plays a role in their activation, thereby aggravating non-allergic inflammation and the severity of asthma.

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Understanding transcriptional identity in Innate Lymphoid Cells (ILC)

Project description:In order to determine the dependency of mature tissue-resident ILCs on combinations of synergistic and antagonising Transcription Factors (TFs), we generated mice with conditional deletions of RORc, RORa and Tbx21 driven from the Id2 allele, utilizing a tamoxifen inducible Cre-recombinase in combination with a tdRFP allele to report Cre-excision (Id2creERT2 x ROSAtdRFP). RFP+ small intestinal ILCs were sorted from the lamina propria digests (gated as CD45+, Lineage negative, CD90+ CD127+, tdRFP+ - see manuscript for full methodological details), from control mice or mice containing loxP flanked alleles for RORc, RORc and RORa or RORc and Tbx21. Four samples of sort-purified ILCs were then subjected to 10X single cell sequencing; - Id2creERT2 - Id2idRORc - Id2idRORc/RORa - Id2idRORc/Tbx21

2021-09-23 | E-MTAB-9795 | biostudies-arrayexpress

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Project description:Single cell RNAseq of human ILCs to investigate potential heterogeneity within ILC subsets

2019-07-01 | GSE114396 | GEO

RNA sequencing of lung innate lymphoid cell (ILC) populations

Project description:A transitory, interleukin-25-responsive, KLRG1high Group 2 innate lymphoid (ILC2) cell subset that migrates to mucosal tissues early during type-2 inflammation was recently identified. This study focuses on understanding the significance of this population in relation to tissue-resident ILC2 cells in the lung and intestine. RNA-sequencing and unbiased pathway analysis revealed the AP-1 factor BATF as a potential modulator of ILC2 cell fate. For RNAseq, KLRG1-postive and KLRG1-neagive populations were sorted and compared.

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