Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA253372 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR1449900.fastq.gz | Fastqsanger.gz | |||
| SRR1449899.fastq.gz | Fastqsanger.gz |
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Project description:Retinoic-acid receptor-related orphan receptor-γt-positive (RORγt+) innate lymphoid cells (ILCs) produce interleukin (IL)-22 and IL-17, which are critical for protective immunity against enteric pathogens. The molecular mechanism underlying the development and survival of RORγt+ ILCs is not thoroughly understood. Here we show that Dedicator of cytokinesis 8 (DOCK8), a scaffolding protein involved in cytoskeletal rearrangement and cell migration, is essential for the protective immunity against Citrobacter rodentium. A comparative RNA sequencing-based analysis reveals an impaired induction of antimicrobial peptides in the colon of DOCK8-deficient mice, which correlates with high susceptibility to infection and a very low number of IL-22-producing RORγt+ ILCs in their GI tract. Furthermore, DOCK8-deficient RORγt+ ILCs are less responsive to IL-7 mediated signaling, more prone to apoptosis and produce less IL-22 due to a defect in IL-23-mediated STAT3 phosphorylation. Our studies reveal an unsuspected role of DOCK8 for the function, generation and survival of RORγt+ ILCs. Control and DOCK8 KO mice were infected with 2X109 CFU of Citrobacter rodentium and day 8 post infection mice were sacrificed and their colons were harvested (n=5) . Total RNA was purified from the infected colons with RNeasy mini kit (Qiagen). RNA sequencing was performed (pooled RNA sample from five mice in each group) at Genomic Core Facility Southwestern Medical Center, University of Texas.
2014-06-25 | E-GEOD-58765 | biostudies-arrayexpress
Project description:Retinoic-acid receptor-related orphan receptor-γt-positive (RORγt+) innate lymphoid cells (ILCs) produce interleukin (IL)-22 and IL-17, which are critical for protective immunity against enteric pathogens. The molecular mechanism underlying the development and survival of RORγt+ ILCs is not thoroughly understood. Here we show that Dedicator of cytokinesis 8 (DOCK8), a scaffolding protein involved in cytoskeletal rearrangement and cell migration, is essential for the protective immunity against Citrobacter rodentium. A comparative RNA sequencing-based analysis reveals an impaired induction of antimicrobial peptides in the colon of DOCK8-deficient mice, which correlates with high susceptibility to infection and a very low number of IL-22-producing RORγt+ ILCs in their GI tract. Furthermore, DOCK8-deficient RORγt+ ILCs are less responsive to IL-7 mediated signaling, more prone to apoptosis and produce less IL-22 due to a defect in IL-23-mediated STAT3 phosphorylation. Our studies reveal an unsuspected role of DOCK8 for the function, generation and survival of RORγt+ ILCs.
2014-06-25 | GSE58765 | GEO
Project description:Dedicator of cytokinesis 8 (DOCK8) deficiency is an autosomal-recessive immunodeficiency disorder that manifests with hyper-IgE syndrome and susceptibility to viral, bacterial, fungal, and parasitic infections as well as malignancy, atopy, and autoimmunity. Up to two-thirds of DOCK8-deficient patients develop chronic mucocutaneous candidiasis (CMC), yet the mechanistic basis for this susceptibility remains elusive. Here, we utilized a mouse model of oral candidiasis to investigate the cellular and molecular mechanisms that drive CMC susceptibility in DOCK8 deficiency. We demonstrate that DOCK8 promotes mucosal fungal clearance via the induction of protective type-17 immune responses. Mechanistically, in the absence of DOCK8, the accumulation of IL-17+ and IL-22+ TCRαβ T cells, γδ T cells, and innate lymphoid cells (ILCs) was markedly decreased in the oral mucosa, driven by increased apoptotic cell death, not impaired cell proliferation or recruitment from the blood. Unexpectedly, DOCK8 was required for the cell-intrinsic acquisition of a type-17 phenotype only in oral mucosal γδ T cells, but not in TCRαβ T cells or ILCs in vivo. Concordantly, mice with conditional DOCK8 deletion in all RORγt-expressing IL-17-producing lymphoid cells, but not in CD4+ T cells alone, were susceptible to oral candidiasis. Moreover, prophylactic administration of the gc family cytokine IL-7 rescued lymphocyte apoptosis, increased the number of IL-17+ and IL-22+ cells, and promoted fungal clearance in DOCK8-deficient mice. Thus, we show that mucosal candidiasis in DOCK8 deficiency is driven by multicellular defects in lymphocyte survival and accumulation resulting in impaired type-17 immunity. IL-7 immunotherapy boosts mucosal type-17 responses and ameliorates fungal susceptibility.
2026-03-27 | GSE293085 | GEO
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.
2015-11-23 | GSE71198 | GEO
Project description:Intestinal innate lymphoid cells (ILCs) contribute to the protective immunity and homeostasis of the gut, and the microbiota are critically involved in shaping ILC function. However, the role of the gut microbiota in regulating ILC development and maintenance still remains elusive. Here, we identified opposing effects on ILCs by two Helicobacter species, Helicobacter apodemus and Helicobacter typhlonius, isolated from immunocompromised mice. We demonstrated that the introduction of both Helicobacter species activated ILCs and induced gut inflammation; however, these Helicobacter species negatively regulated RORγt+ Group 3 ILCs (ILC3s), especially T-bet+ ILC3s, and diminished their proliferative capacity. Thus, these findings underscore a previously unknown dichotomous regulation of ILC3s by Helicobacter species, and may serve as a model for further investigations to elucidate the host-microbe interactions that critically sustain the maintenance of intestinal ILC3s.
2019-11-18 | GSE136171 | GEO
Project description:The aim of this study was to analyze the global transcriptional profiles of small intestine (SI) Innate Lymphoid Cells (ILCs) expressing the NK cell marker NKp46. Based on differential expression of the RORgt transcription factor SI NKp46+ ILCs can be divided in NKp46+RORgt- and NKp46+RORgt+ cells. While NKp46+RORgt- cells produce IFN-g, like conventional Natural Killer (NK) cells, NKp46+RORgt+ cells secrete IL-22, like Lymphoid Tissue inducer (LTi) cells. We compared the global transcriptional profiles of both NKp46+RORgt- and NKp46+RORgt+ cells to conventional splenic NK cells and to SI NKp46-RORgt+ cells, which contain adult LTi cells. By following this approach, we showed that SI NKp46+RORγt- ILCs correspond to SI NK cells. We also identified a transcriptional program conserved in adult SI NKp46+RORγt+, NKp46-RORγt+ ILCs and fetal LTi. The various ILC cell populations analyzed in this study were isolated from C57BL/6 RORc(gt)+/GFP reporter mice. SI NKp46+RORγt- (NKp46+GFP-) cells, SI NKp46+RORγt+ cells (NKp46+GFPlow and NKp46+GFPhigh cells) and NKp46-RORγt+ ILCs, including adult LTi cells , were sorted by flow cytometry from CD3- lamina propria cells of small intestine (SI) of RORc(γt)+/GFP reporter mice . Splenic NKp46+RORγt- (NKp46+GFP-) cells were also sorted as the reference for conventional NK cells. Two replicates of each populations were produced and analyzed.
2011-06-20 | E-GEOD-29777 | biostudies-arrayexpress
Project description:Mutations in the DOCK8 gene cause an autosomal recessive form of hyper-immunoglobulin E syndrome, characterised by chronic immunodeficiency with persistent microbial infection and increased incidence of malignancy. These manifestations suggest a defect in cytotoxic lymphocyte function and immune surveillance. However, how DOCK8 regulates NK cell-driven immune responses remains unclear. Here, we demonstrate that DOCK8 regulates NK cell cytotoxicity and cytokine production in response to target cell engagement or receptor ligation. Genetic ablation of DOCK8 in human NK cells attenuated cytokine transcription and secretion through inhibition of Src family kinase activation, particularly Lck, downstream of target cell engagement or NKp30 ligation. PMA/Ionomycin treatment of DOCK8 deficient NK cells rescued cytokine production, indicating a defect proximal to receptor ligation. Importantly, NK cells from DOCK8 deficient patients had attenuated production of IFNγ and TNFα upon NKp30 stimulation. Taken together, we reveal a novel molecular mechanism by which DOCK8 regulates NK cell driven immunity.
2017-09-15 | GSE101467 | GEO
Project description:Immune responses are initiated by activation of innate lymphoid cells (ILCs), T-bet-dependent natural killer and ILC1 cells, GATA-3-dependent ILC2 cells, and RORγt-dependent ILC3 cells. Despite accumulated knowledge of translational regulation in ILCs, comprehensive impact of mRNA decay on ILCs has not been clarified yet. CNOT3 is a main subunit of the CCR4-NOT complex which mainly destabilizes mRNAs by poly (A) deadenylation in eukaryotes. Here, we showed that CNOT3 is required for cell survival of all ILCs and that the absence of CNOT3 promoted T-bet and RORγt expression due to increased stability of Tbx21 and Rorc mRNAs in ILC2 cells and enabled them to produce granzyme B and IL-22. Likewise, Th1 and Th17 skewing was induced in CD4 T cells lacking CNOT3. Furthermore, CNOT3 in each ILC subset contributes to their type-specific immune responses. Thus, the CCR4-NOT complex controls ILC differentiation by inhibiting the potential for type 1 and 3 immunity.
2026-04-25 | GSE263342 | GEO
Project description:Immune responses are initiated by activation of innate lymphoid cells (ILCs), T-bet-dependent natural killer and ILC1 cells, GATA-3-dependent ILC2 cells, and RORγt-dependent ILC3 cells. Despite accumulated knowledge of translational regulation in ILCs, comprehensive impact of mRNA decay on ILCs has not been clarified yet. CNOT3 is a main subunit of the CCR4-NOT complex which mainly destabilizes mRNAs by poly (A) deadenylation in eukaryotes. Here, we showed that CNOT3 is required for cell survival of all ILCs and that the absence of CNOT3 promoted T-bet and RORγt expression due to increased stability of Tbx21 and Rorc mRNAs in ILC2 cells and enabled them to produce granzyme B and IL-22. Likewise, Th1 and Th17 skewing was induced in CD4 T cells lacking CNOT3. Furthermore, CNOT3 in each ILC subset contributes to their type-specific immune responses. Thus, the CCR4-NOT complex controls ILC differentiation by inhibiting the potential for type 1 and 3 immunity.
2026-04-25 | GSE263340 | GEO
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