Group 3 innate lymphoid cells mediate early protective immunity against Mycobacterium tuberculosis
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE131031 | GEO | 2019/05/11
REPOSITORIES: GEO
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Project description: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. 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
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
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.
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Project description: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.
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Project description:Group 2 innate lymphoid cells (ILC2s) are linked to type 2 immune diseases but can also molecularly change phenotype and provide type 1 immunity towards pathogens. Here we identify an ILC2 subset which can convert into IL-17 producing NKp44‒ ILC3-like cells. c-Kit and CCR6 define this ILC2 subpopulation which exhibit ILC3 features, including RORγt, which enables the conversion into IL-17 producing cells in response to IL-1β and IL-23. We also report a novel but critical role for TGF-β in promoting the conversion of c-kit‒ ILC2s into RORγt expressing c-Kit+ ILC2s by inducing the upregulation of IL23R, CCR6 and KIT mRNA in these cells. This switch was dependent on RORγt and down-regulation of GATA-3. IL-4 was able to reverse this event supporting a role for this cytokine in maintaining ILC2 identity. Notably, this plasticity has physiological relevance as a subset of RORγt+ ILC2s express the skin homing receptor CCR10 and the frequencies of IL-17‒producing ILC3s are increased at the expense of ILC2s within the lesional skin of psoriatic patients compared to healthy individuals.
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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.
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Project description:Ror gamma t-deficient mice lack group 3 Innate Lymphoid Cells (ILC3s) and as a result have increased tissue damage and diminished tissue repair in response to insult. To identify repair programs associated with ILC3 presence the transcriptomes of small intestinal stem cells exposed to damage in the presence or absence of ILC3 were compared. Small intestinal damage was induced in Ror gamma t-deficient Lgr5 reporter mice and littermate controls. Small intestinal epithelial stem cells were purified at days 1 and 4 after damage and subjected to RNA sequencing.
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Project description:Group 3 innate lymphoid cells (ILC3s) produce interleukin (IL)-22 and, together with other cells in the gut, orchestrate to mount productive host immunity against bacterial infection. However, the role of ILC3s in Salmonella enterica serovar Typhimurium (S. Typhimurium) infection, which causes foodborne enteritis in humans, remains elusive. Here, we show that S. Typhimurium exploit ILC3-produced IL-22 to promote its infection. Specifically, S. Typhimurium secrete flagellin through activation of the TLR5-Myd88-IL-23 signaling pathway in antigen presenting cells (APCs) to selectively enhance IL-22 production by ILC3s, but not T cells. Deletion of ILC3s but not T cells in mice led to better control of S. Typhimurium infection. We also show that S. Typhimurium can invade ILC3s directly and cause caspase-1-mediated ILC3 pyroptosis independently of flagellin. Genetic ablation of Casp1 in mice leads to increased ILC3 survival and IL-22 production, and enhanced S. Typhimurium infection. Collectively, our data suggest a key host defense mechanism against S. Typhimurium infection via induction of ILC3 death to limit intracellular bacteria and reduce IL-22 production.
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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.
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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.
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