Control of Peripheral Tolerance by Regulatory T Cell-Intrinsic Notch Signaling
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE71343 | GEO | 2015/07/25
SECONDARY ACCESSION(S): PRJNA290928
REPOSITORIES: GEO
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Project description:Notch receptors direct the differentiation of T helper (Th) cell subsets, but their influence on regulatory T (TR) cell responses is obscure. Interruption of Notch signaling in TR cells resulted in a super-regulatory phenotype, with suppression of TR cell Th1 programming and apoptosis as well as Th1 cell responses in systemic inflammation. In contrast, gain of function Notch1 signaling in TR cells resulted in lymphoproliferation, dysregulated Th1 responses and autoimmunity. To determine mechanisms by which Notch signaling may alter TR cell function, we compared the transcriptional profiles of splenic TR cells of Foxp3EGFPCre mice with those of Foxp3EGFPCreR26N1c/N1c (gain of function Notch signaling), Foxp3EGFPCreRBPJ∆/∆ (loss of function canonical Notch signaling), and Foxp3EGFPCreR26N1c/N1cRBPJ∆/∆ mice (gain of function/canonical loss of function Notch signaling). Regulatory T cells are isolated from the spleen of 6 weeks old males, based on the expression of CD3, TCRbeta, CD4 and GFP (Foxp3), after Red blood cell lysis by ACK and gate on lineage negative (CD8, B220, CD11b, CD11c, Gr1) cells. To reduce variability and increase cell number, cells from multiple mice were pooled for sorting and at least three replicates were generated for all groups. RNA from 4.0-5.0x104 cells was amplified, labeled and hybridized to Affymetrix Mouse Gene 1.0 ST Arrays
2015-07-25 | E-GEOD-71343 | biostudies-arrayexpress
Project description:NOTCH1 gain-of-function mutations are recurrent in B cell chronic lymphocytic leukemia (B-CLL), where they are associated with accelerated disease progression and refractoriness to chemotherapy. The specific role of NOTCH1 in the development and progression of this malignancy is unclear. Herein we assess the impact of loss of Notch signaling and pathway hyperactivation in an in vivo mouse model of CLL (IgH.TEm) that faithfully recapitulates many features of the human pathology. Ablation of canonical Notch signaling using conditional gene inactivation of RBP-J in immature hematopoietic or B cell progenitors delayed CLL induction and reduced incidence of mice developing disease. In contrast, forced expression of a dominant active form of Notch resulted in more animals developing CLL with early disease onset. Comparative analysis of gene expression and epigenetic features of Notch gain-of-function and control CLL cells revealed direct and indirect regulation of cell cycle-associated genes, which led to increased proliferation of Notch gain-of-function CLL cells in vivo. These results demonstrate that Notch signaling facilitates disease initiation and promotes CLL cell proliferation and disease progression.
2020-12-19 | GSE160510 | GEO
Project description:NOTCH1 gain-of-function mutations are recurrent in B cell chronic lymphocytic leukemia (B-CLL), where they are associated with accelerated disease progression and refractoriness to chemotherapy. The specific role of NOTCH1 in the development and progression of this malignancy is unclear. Herein we assess the impact of loss of Notch signaling and pathway hyperactivation in an in vivo mouse model of CLL (IgH.TEm) that faithfully recapitulates many features of the human pathology. Ablation of canonical Notch signaling using conditional gene inactivation of RBP-J in immature hematopoietic or B cell progenitors delayed CLL induction and reduced incidence of mice developing disease. In contrast, forced expression of a dominant active form of Notch resulted in more animals developing CLL with early disease onset. Comparative analysis of gene expression and epigenetic features of Notch gain-of-function and control CLL cells revealed direct and indirect regulation of cell cycle-associated genes, which led to increased proliferation of Notch gain-of-function CLL cells in vivo. These results demonstrate that Notch signaling facilitates disease initiation and promotes CLL cell proliferation and disease progression.
2020-12-19 | GSE160508 | GEO
Project description:NOTCH1 gain-of-function mutations are recurrent in B cell chronic lymphocytic leukemia (B-CLL), where they are associated with accelerated disease progression and refractoriness to chemotherapy. The specific role of NOTCH1 in the development and progression of this malignancy is unclear. Herein we assess the impact of loss of Notch signaling and pathway hyperactivation in an in vivo mouse model of CLL (IgH.TEm) that faithfully recapitulates many features of the human pathology. Ablation of canonical Notch signaling using conditional gene inactivation of RBP-J in immature hematopoietic or B cell progenitors delayed CLL induction and reduced incidence of mice developing disease. In contrast, forced expression of a dominant active form of Notch resulted in more animals developing CLL with early disease onset. Comparative analysis of gene expression and epigenetic features of Notch gain-of-function and control CLL cells revealed direct and indirect regulation of cell cycle-associated genes, which led to increased proliferation of Notch gain-of-function CLL cells in vivo. These results demonstrate that Notch signaling facilitates disease initiation and promotes CLL cell proliferation and disease progression.
2020-12-19 | GSE147836 | GEO
Project description:Notch signaling is frequently hyperactivated in breast cancer, but how the enhanced signaling contributes to the tumor process is less well understood. In this report, we identify the proinflammatory cytokine interleukin-6 (IL-6) as a novel Notch target in breast tumor cells. Enhanced Notch signaling upregulated IL-6 expression at the transcriptional level, leading to activation of autocrine and paracrine JAK/STAT signaling. IL-6 upregulation was mediated by non-canonical Notch signaling, as it could be effectuated by a cytoplasmically localized Notch intracellular domain and was independent on the DNA-binding protein CSL. Instead, Notch-mediated IL-6 upregulation was controlled by two other factors: IKKβ, a protein in the NF-kB signaling cascade, and p53. Activation of IL-6 by Notch required IKKβ function, but interestingly, did not engage canonical NF-κB signaling, in contrast to IL-6 activation by inflammatory agents such as tumor necrosis factor, which requires canonical NF-κB signaling. With regard to p53 status, IL-6 expression was upregulated by Notch when p53 was mutated or lost, but restoring wildtype 53 into p53-mutated or -deficient cells abrogated the IL-6 upregulation. Furthermore, Notch-induced genome-wide transcriptomes from p53 wildtype and -mutated breast tumor cell lines differed extensively, and in a subset of genes upregulated by Notch in a p53-mutant cell line, upregulation was reduced by wildtype p53. In conclusion, we identify IL-6 as a novel non-canonical Notch target gene, and reveal roles for p53 and IKKβ in non-canonical Notch signaling in breast cancer and in the generation of cell context-dependent diversity in the Notch signaling output. 30 microarray samples consisting of MCF7 (ER+, wild-type p53, luminal type B breast cancer) and MDA-MB-231 (ER-, mutated p53, basal breast cancer) cells cultured on immobilized 1 μg/ml JAGGED1-Fc or 1 μg/ml DLL4-Fc or 1 μg/ml Fc control with or without 5 μM DAPT for 6 hours in 3 biological replicates.
2012-06-29 | E-GEOD-36051 | biostudies-arrayexpress
Project description:Notch signaling is frequently hyperactivated in breast cancer, but how the enhanced signaling contributes to the tumor process is less well understood. In this report, we identify the proinflammatory cytokine interleukin-6 (IL-6) as a novel Notch target in breast tumor cells. Enhanced Notch signaling upregulated IL-6 expression at the transcriptional level, leading to activation of autocrine and paracrine JAK/STAT signaling. IL-6 upregulation was mediated by non-canonical Notch signaling, as it could be effectuated by a cytoplasmically localized Notch intracellular domain and was independent on the DNA-binding protein CSL. Instead, Notch-mediated IL-6 upregulation was controlled by two other factors: IKKβ, a protein in the NF-kB signaling cascade, and p53. Activation of IL-6 by Notch required IKKβ function, but interestingly, did not engage canonical NF-κB signaling, in contrast to IL-6 activation by inflammatory agents such as tumor necrosis factor, which requires canonical NF-κB signaling. With regard to p53 status, IL-6 expression was upregulated by Notch when p53 was mutated or lost, but restoring wildtype 53 into p53-mutated or -deficient cells abrogated the IL-6 upregulation. Furthermore, Notch-induced genome-wide transcriptomes from p53 wildtype and -mutated breast tumor cell lines differed extensively, and in a subset of genes upregulated by Notch in a p53-mutant cell line, upregulation was reduced by wildtype p53. In conclusion, we identify IL-6 as a novel non-canonical Notch target gene, and reveal roles for p53 and IKKβ in non-canonical Notch signaling in breast cancer and in the generation of cell context-dependent diversity in the Notch signaling output.
2012-06-30 | GSE36051 | GEO
Project description:Thyroid hormone (TH) and TH receptors (TRs) α and β act by binding to TH response elements (TREs) in regulatory regions of target genes. This nuclear signaling is established as the canonical pathway for TH action. In addition, however, TRs can activate intra-cellular second messenger signaling pathways. Whether such non-canonical TR signaling is physiologically relevant in vivo is unknown. Here we generated knock-in mice with a mutation in the TR DNA-binding domain that abrogates binding to DNA and TREs and leads to a complete loss of canonical TH action. We show that several important physiological TH effects are preserved despite disrupted DNA-binding, most notably heart rate, body temperature, blood glucose and triglyceride concentration, all of which were regulated by non-canonical TR signaling. Additionally, we confirm that TRE-binding defective TRβ leads to disruption of the hypothalamic-pituitary-thyroid axis with resistance to TH, while mutation of TRα causes a severe delay in skeletal development, showing TRE-mediated and tissue-specific canonical signaling. Our findings provide first in vivo evidence that non-canonical TR signaling exerts important cardiometabolic effects, which are clearly separated from canonical actions. Consequently, these data challenge the current paradigm that TH action is exclusively mediated through regulation of gene transcription at the nuclear level.
2017-11-01 | GSE104877 | GEO
Project description:Primary immune regulatory disorders (PIRD) are a group of disorders characterized by immune dysregulation, presenting with a wide range of clinical disease including autoimmunity, autoinflammation, or lymphoproliferation. Autosomal dominant germline gain-of-function (GOF) variants in STAT3 result in a PIRD with a broad spectrum of clinical features and prior studies have documented a decreased frequency of Foxp3+ regulatory T (Treg) cells and an increased frequency of Th17 cells is some patients. However, the precise mechanisms of disease pathogenesis in STAT3 GOF syndrome remain largely unknown. We developed a knock-in mouse model harboring a de novo pathogenic human STAT3 variant (p.G421R) and found these mice developed T cell dysregulation, lymphoproliferation and CD4+ Th1 cell skewing. Surprisingly, Treg cell numbers, phenotype, and function remained largely intact, however mice had a selective deficiency in the generation of iTreg cells. In parallel, we performed single-cell RNA-sequencing on T cells from patients with STAT3 GOF syndrome. We demonstrate only minor changes in the Treg cell transcriptional signature and an expanded, effector CD8+ T cell population. Together, these finding suggest Treg cells are not the primary driver of disease and highlight the importance of preclinical models in the study of disease mechanisms in rare PIRD.
2022-10-14 | GSE207935 | GEO
Project description:Primary immune regulatory disorders (PIRD) are a group of disorders characterized by immune dysregulation, presenting with a wide range of clinical disease including autoimmunity, autoinflammation, or lymphoproliferation. Autosomal dominant germline gain-of-function (GOF) variants in STAT3 result in a PIRD with a broad spectrum of clinical features and prior studies have documented a decreased frequency of Foxp3+ regulatory T (Treg) cells and an increased frequency of Th17 cells is some patients. However, the precise mechanisms of disease pathogenesis in STAT3 GOF syndrome remain largely unknown. We developed a knock-in mouse model harboring a de novo pathogenic human STAT3 variant (p.G421R) and found these mice developed T cell dysregulation, lymphoproliferation and CD4+ Th1 cell skewing. Surprisingly, Treg cell numbers, phenotype, and function remained largely intact, however mice had a selective deficiency in the generation of iTreg cells. In parallel, we performed single-cell RNA-sequencing on T cells from patients with STAT3 GOF syndrome. We demonstrate only minor changes in the Treg cell transcriptional signature and an expanded, effector CD8+ T cell population. Together, these finding suggest Treg cells are not the primary driver of disease and highlight the importance of preclinical models in the study of disease mechanisms in rare PIRD.
2022-10-14 | GSE207934 | GEO
Project description:The sensory epithelium of the cochlea is a specialized structure responsible for the perception of sound. While much is understood about the development of the mechanosensory hair cells found within this epithelium, little is known about the development of the glial-like supporting cells. Here, we provide evidence that in addition to its well-characterized inhibitory function, canonical Notch signaling plays a positive, instructive role in the differentiation of supporting cells. Using γ-secretase inhibitor DAPT to acutely block canonical Notch signaling, we identified a cohort of Notch-regulated supporting cell-specific genes, with diverse functions in cell signaling, cell differentiation, neuronal innervation and synaptogenesis.
2016-02-01 | GSE67085 | GEO