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Group 3 innate lymphoid cells continuously require the transcription factor GATA3 after commitment

ABSTRACT: GATA3 is indispensable for the development of all IL-7Rα-expressing innate lymphoid cells (ILCs) and maintenance of type 1 ILCs (ILC1s) and type 2 ILCs (ILC2s). However, the importance of low GATA3 expression in type 3 ILCs (ILC3s) is still elusive. Here, we report that GATA3 regulates homeostasis of ILC3s by controlling IL-7Rα expression. In addition, GATA3 is critical for the development of NKp46+ ILC3 subset partially through regulating the balance between T-bet and RORγt. Genome-wide analyses indicate that while GATA3 positively regulates CCR6+ and NKp46+ ILC3 subset-specific genes in respective lineages, it negatively regulates CCR6+ ILC3-specific genes in NKp46+ ILC3s. Furthermore, GATA3 regulates IL-22 production in both CCR6+ and NKp46+ ILC3s. Thus, low GATA3 expression is critical for the development and function of ILC3 subsets.

ORGANISM(S): Mus musculus

PROVIDER: GSE71198 | GEO | 2015/11/23

SECONDARY ACCESSION(S): PRJNA290564

REPOSITORIES: GEO

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Group 3 innate lymphoid cells continuously require the transcription factor GATA3 after commitment

Project description:GATA3 is indispensable for the development of all IL-7RÎ±-expressing innate lymphoid cells (ILCs) and maintenance of type 1 ILCs (ILC1s) and type 2 ILCs (ILC2s). However, the importance of low GATA3 expression in type 3 ILCs (ILC3s) is still elusive. Here, we report that GATA3 regulates homeostasis of ILC3s by controlling IL-7RÎ± expression. In addition, GATA3 is critical for the development of NKp46+ ILC3 subset partially through regulating the balance between T-bet and RORÎ³t. Genome-wide analyses indicate that while GATA3 positively regulates CCR6+ and NKp46+ ILC3 subset-specific genes in respective lineages, it negatively regulates CCR6+ ILC3-specific genes in NKp46+ ILC3s. Furthermore, GATA3 regulates IL-22 production in both CCR6+ and NKp46+ ILC3s. Thus, low GATA3 expression is critical for the development and function of ILC3 subsets. To identify GATA3 regulated genes in total ILC3s with RNA-Seq; To identify unique genes expressed by CCR6+ ILC3 or NKp46+ ILC3 and GATA3 regulated genes within these two ILC3 subsets with RNA-Seq; To identify GATA3 direct binding sites in ILC3s, ILC2s and Th2 cells with ChIP-Seq.

2015-11-23 | E-GEOD-71198 | biostudies-arrayexpress

Metabolite - sensing receptor Ffar2 regulates colonic group 3 innate lymphoid cells and gut immunity

Project description:Group 3 innate lymphoid cells (ILC3s) sense environmental signals that are critical for gut homeostasis and host defense. However, the metabolite-sensing G-protein-coupled receptors that regulate colonic ILC3s remain poorly understood. We found that colonic ILC3s expressed Ffar2, a microbial metabolite-sensing receptor, and that Ffar2 agonism promoted ILC3 expansion and function. Deletion of Ffar2 in ILC3s decreased their in situ proliferation and ILC3-derived IL-22 production. This led to impaired gut epithelial function characterized by altered mucus-associated proteins and antimicrobial peptides and increased susceptibility to colonic injury and bacterial infection. Ffar2 increased IL-22+ CCR6+ ILC3s and influenced ILC3 abundance in colonic lymphoid tissues. Ffar2 agonism differentially activated AKT or ERK signaling and increased ILC3-derived IL-22 via an AKT and STAT3 axis. Our findings demonstrate that Ffar2 regulates colonic ILC3 proliferation and function in a cell-intrinsic manner and identifies an ILC3-receptor signaling pathway regulating gut inflammatory tone and pathogen defense.

2019-09-16 | GSE137508 | GEO

IL-15 sustains IL-7R independent ILC2 and ILC3 development

Project description:ILC3 contain 3 well-defined subsets, CCR6+ ILC3, NKp46+ ILC3, and CCR6–NKp46– DN ILC3. These subsets had not previously been transcriptionally compared and the extent to which they had shared or unique transcriptional profiles remained unclear. We used microarray to determine transcriptional differences between these 3 subsets and to find putative factors that support the survival of CCR6+ ILC3 during cytokine depletion.

2017-02-10 | GSE92693 | GEO

Intermediate GATA3 expression renders a noncanonical ILC population in skin essential for hair follicle recycling

Project description:We find that the expression of GATA3 in skin ILCs is significantly lower than in conventional ILC2s of other tissues, indicating that the regulatory role of GATA3 may be different. Indeed, skin ILCs are still maintained after inducing Gata3 depletion in Gata3fl/flCreERT2 mice, when all ILC2s were gone. In addition, about 70% skin ILCs are found to experience RORγt expression as reflected by RORγt fate-mapping. And, conditional Gata3 depletion in the RORγt fate-mapped skin ILCs does not affect their number as well. Therefore, in contrast to conventional ILC2s, GATA3 is not required for skin ILCs for their maintenance. The RORγt fate-mapped skin ILCs have exhibited ILC3-like features. Single-cell transcriptome analysis further reveals that skin ILCs converge on a Ccr6+ ILC3-like state and an Il1rl1+ ILC2-like state. The regulatory role of GATA3 is crucial in the ILC3-like skin ILCs. It promotes the expression of their featured genes, while suppresses the expression of ILC2-like skin ILC featured genes. These ILC3-like skin ILCs locate in close proximity to hair follicles. During hair follicle recycling they migrate from isthmus to suprabulbar to promote the hair follicle growth. Whereas in absence of Gata3, the ILC3-like skin ILCs exhibit defective migration to the suprabulbar and reduced expression of the featured genes in this process. Together, our study evidence that skin ILCs are alternative to conventional ILC2s. In particular, we shed light on the function of GATA3 in promoting the specific gene expression in ILC3-like skin ILCs and regulating their crucial roles in hair follicle recycling, which will improve our knowledge about the involvement of ILCs in maintaining homeostasis of skin.

2022-02-05 | GSE195973 | GEO

A cis-element at the Rorc locus regulates the development of type 3 innate lymphoid cells

Project description:As an important early source of IL-17A and IL-22 in immune responses, type 3 innate lymphoid cells (ILC3s) are critically regulated by the transcription factor retinoic-acid-receptor-related orphan receptor gamma t (RORγt). Previously, we have identified a crucial role of the conserved non-coding sequence 9 (CNS9), located at +5,802 to +7,963 bp of the Rorc gene, in directing T helper 17 differentiation and related autoimmune disease. However, whether cis-acting elements regulate RORγt expression in ILC3s is unknown. Here we show that CNS9 deficiency in mice not only decreases ILC3 signature gene expression and increases ILC1-gene expression features in total ILC3s, but also leads to generation of a distinct CD4+NKp46+ ILC3 population, though the overall numbers and frequencies of RORγt+ ILC3s are not affected. Mechanistically, CNS9 deficiency selectively decreases RORγt expression in ILC3s, which thus alters ILC3 gene expression features and promotes cell-intrinsic generation of CD4+NKp46+ ILC3 subset. Our study thus identifies CNS9 as an essential cis-regulatory element controlling the lineage stability and plasticity of ILC3s through modulating expression levels of RORγt protein.

2023-02-28 | GSE225928 | GEO

RNA-seq of mouse small intestinal CCR6+ group3 innate lymphoid cells

Project description:CCR6+NKp46- ILC3 were isolated from the small intestine of untreated mice by flow cytometry. ILC3 from 3 mice were pooled for subsequent RNA sequencing.

2019-10-11 | E-MTAB-8387 | biostudies-arrayexpress

Analyses of ILC3s from the mesenteric lymph nodes (LN)

Project description:Analyses of ILC3s in Rorc floxed control and Id2iÎ?RORÎ³t mice following daily treatments of tamoxifen for two weeks. Cells were sort purified as lineage negative, CD127+ CD90.2+ CCR6+ ST2- CCR6+ ILCs were sorted from the mesenteric LN of Rorc floxed control and Id2iÎ?RORÎ³t mice following daily treatments of tamoxifen for two weeks.

2016-02-15 | E-GEOD-76201 | biostudies-arrayexpress

Genome Wide Chromatin Mapping of Aiolos accessability and H3K27ac histone modifications in transfected MNK3 cells

Project description:Innate lymphoid cells (ILCs) are tissue-resident lymphocytes subdivided into ILC1s, ILC2s and ILC3s based on core regulatory programs and signature cytokines secreted. ILCs exhibit functional plasticity: for instance, human IL-22-producing ILC3s convert into IFN-γ-producing ILC1-like in vitro. Whether this conversion occurs in vivo is unclear. Using flow cytometry, mass cytometry and scRNAseq, here we found that ILC3s and ILC1s occupy opposite ends of a spectrum including discrete subsets in human tonsils. RNA velocity suggested strong directionality toward ILC1s for one ILC3-ILC1 intermediate cluster. Clonal analysis revealed graded ability of ILC3-ILC1 subsets to convert into ILC1-like cells. When examined in humanized mice, ILC3 acquisition of ILC1 features showed tissue-dependency. In chromatin studies, Aiolos emerged as a nuclear factor that cooperates with Tbet to repress evolutionarily conserved regulatory elements active in ILC3s. The human intestine also exhibited an ILC3–ILC1 transitional population. We conclude that conversion of ILC3s to ILC1-like occurs in vivo in human tissues, and that tissue factors and Aiolos are crucial for this process.

2019-05-07 | GSE130774 | GEO

Microarray data from human ILC transitional populations

2019-05-07 | GSE130773 | GEO

RNA-Seq from human ILC transitional populations

2019-05-07 | GSE130772 | GEO