Investigating the epigenetic and transciptional changes induced in tolerant T cells [DNAse-seq]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE147266 | GEO | 2020/06/11
REPOSITORIES: GEO
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Project description:Here we investigated the underlying mechanisms causing the suppression of normal immune responses when T cells are rendered anergic by tolerance induction. By performing an integrated analysis of signaling, epigenetic modifications and gene expression, we demonstrate that immunological tolerance is established when both signaling to and epigenetic priming of immune response genes are weakened. In parallel, epigenetic priming of immune-repressive genes is boosted, rendering them sensitive to low levels of signaling below the threshold needed to activate immune response genes.
2020-06-11 | GSE147267 | GEO
Project description:Training and priming of innate immune cells involve preconditioning by PAMPs, DAMPs and/or cytokines that elicits stronger induction of inflammatory genes upon secondary challenge. Previous models distinguish training and priming based upon whether immune activation returns to baseline prior to secondary challenge. Tolerance is a protective mechanism whereby potent stimuli induce refractoriness to secondary challenge. Training and priming are important for innate memory responses that protect against infection, efficacy of vaccines, and maintaining innate immune cells in a state of readiness; tolerance prevents toxicity from excessive immune activation. Dysregulation of these processes can contribute to pathogenesis of autoimmune/inflammatory conditions, post-COVID-19 hyperinflammatory states, or sepsis- associated immunoparalysis. Training, priming and tolerance regulate similar ‘signature’ inflammatory genes such as TNF, IL6 and IL1B and utilize overlapping epigenetic mechanisms. We review how interferons (IFNs), best known for activating Jak-STAT signaling and interferon- stimulated genes, also play a key role regulating training, priming and tolerance via chromatin- mediated mechanisms. We present new data on how monocyte-to-macrophage differentiation modulates IFN-g-mediated priming, changes AP-1 and CEBP activity, and attenuates superinduction of inflammatory genes. We present a ‘training-priming continuum’ model that integrates IFN-mediated priming into current concepts about training and tolerance and proposes a central role for STAT1 and IRF1.
2024-05-22 | GSE262912 | GEO
Project description:Training and priming of innate immune cells involve preconditioning by PAMPs, DAMPs and/or cytokines that elicits stronger induction of inflammatory genes upon secondary challenge. Previous models distinguish training and priming based upon whether immune activation returns to baseline prior to secondary challenge. Tolerance is a protective mechanism whereby potent stimuli induce refractoriness to secondary challenge. Training and priming are important for innate memory responses that protect against infection, efficacy of vaccines, and maintaining innate immune cells in a state of readiness; tolerance prevents toxicity from excessive immune activation. Dysregulation of these processes can contribute to pathogenesis of autoimmune/inflammatory conditions, post-COVID-19 hyperinflammatory states, or sepsis- associated immunoparalysis. Training, priming and tolerance regulate similar ‘signature’ inflammatory genes such as TNF, IL6 and IL1B and utilize overlapping epigenetic mechanisms. We review how interferons (IFNs), best known for activating Jak-STAT signaling and interferon- stimulated genes, also play a key role regulating training, priming and tolerance via chromatin- mediated mechanisms. We present new data on how monocyte-to-macrophage differentiation modulates IFN-g-mediated priming, changes AP-1 and CEBP activity, and attenuates superinduction of inflammatory genes. We present a ‘training-priming continuum’ model that integrates IFN-mediated priming into current concepts about training and tolerance and proposes a central role for STAT1 and IRF1.
2024-05-22 | GSE262911 | GEO
Project description:Trained immunity and immune tolerance have been identified as long-term response patterns of the innate immune system. The causes of these opposing reactions remain elusive. Here we report about differential inflammatory responses of microglial cells derived from neonatal mouse brain to increasing doses of the endotoxin LPS. Prolonged priming with ultra-low LPS doses provokes trained immunity, i.e. increased production of pro-inflammatory mediators in comparison to the unprimed control. In contrast, priming with high doses of LPS induces immune tolerance implying decreased production of inflammatory mediators and pronounced release of anti-inflammatory cytokines. Investigation of the signaling processes and cell functions involved in these memory-like immune responses reveals essential role of phosphoinositide 3-kinase γ (PI3Kγ), one of the phosphoinositide 3-kinase species highly expressed in innate immune cells. Together, our data suggest profound influence of preceding contacts with pathogens on the immune response of microglia. The impact of these interactions – trained immunity or immune tolerance - appears to be shaped by pathogen dose.
2019-12-05 | GSE137741 | GEO
Project description:T cell anergy is one of the mechanisms contributing to peripheral tolerance, particularly in the context of progressively growing tumors and in tolerogenic treatments promoting allograft acceptance. We recently reported that early growth response gene 2 (Egr2) is a critical transcription factor for the induction of anergy in vitro and in vivo, which was identified based on its ability to regulate the expression of inhibitory signaling molecules diacylglycerol kinase (DGK)-a and -z. We reasoned that other transcriptional targets of Egr2 might encode additional factors important for T cell anergy and immune regulation. Thus, we conducted two sets of genome-wide screens: gene expression profiling of wild type versus Egr2-deleted T cells treated under anergizing conditions, and a ChIP-Seq analysis to identify genes that bind Egr2 in anergic cells. Merging of these data sets revealed 49 targets that are directly regulated by Egr2. Among these are inhibitory signaling molecules previously reported to contribute to T cell anergy, but unexpectedly, also cell surface molecules and secreted factors, including lymphocyte-activation gene 3 (Lag3), Class-I-MHC-restricted T cell associated molecule (Crtam), Semaphorin 7A (Sema7A), and chemokine CCL1. These observations suggest that anergic T cells might not simply be functionally inert, and may have additional functional properties oriented towards other cellular components of the immune system. T cell-specific Egr2 deletion was mediated by use of a Cre-expressing adenovirus and a CAR Tg x Egr2flox/flox mouse in which CAR is expressed exclusively in the T cell compartment from a Lck promoter/CD2 enhancer cassette. OVA-specific Th1 cell clones were generated from CAR Tg x Egr2flox/flox mice. CAR Tg x Egr2flox/flox Th1 T cells were infected with an empty (EV) or a Cre-expressing adenovirus. Upon confirmation of Egr2 deletion by immunoblot, the T cells were left untreated (Control) or anergized (Anergic) by immobilized anti-CD3 for 16 hours, and microarray was conducted after 1 day of rest in culture medium. The microarray analysis was performed three times using three sets of independently manipulated samples
2013-04-21 | E-GEOD-46242 | biostudies-arrayexpress
Project description:Pathogen encounter results in long-lasting epigenetic imprinting that shapes diseases caused by heterologous pathogens. The breadth of this innate immune memory is of particular interest in the context of respiratory pathogens with increased pandemic potential and wide-ranging impact on global health. Here, we investigated epigenetic imprinting across cell lineages in a disease relevant murine model of SARS-CoV-2 recovery. Past SARS-CoV-2 infection resulted in increased chromatin accessibility of type I interferon (IFN-I) related transcription factors and transcriptionally poised antiviral genes in airway-resident macrophages. Mechanistically, viral pattern recognition and canonical IFN-I signaling were required for establishment of this innate immune memory and resulting augmented secondary antiviral responses. SARS-CoV-2-associated innate immune memory in airway-resident macrophages was necessary and sufficient to ameliorate secondary disease caused by the heterologous respiratory pathogen influenza A virus. Insights into how innate immune memory shapes outcome of heterologous secondary diseases could facilitate the development of broadly effective therapeutic strategies.
2024-10-02 | GSE264683 | GEO
Project description:Investigating the epigenetic and transciptional changes induced in tolerant T cells
| PRJNA613647 | ENA
Project description:Pathogen encounter results in long-lasting epigenetic imprinting that shapes diseases caused by heterologous pathogens. The breadth of this innate immune memory is of particular interest in the context of respiratory pathogens with increased pandemic potential and wide-ranging impact on global health. Here, we investigated epigenetic imprinting across cell lineages in a disease relevant murine model of SARS-CoV-2 recovery. Past SARS-CoV-2 infection resulted in increased chromatin accessibility of type I interferon (IFN-I) related transcription factors and transcriptionally poised antiviral genes in alveolar macrophages. Mechanistically, viral pattern recognition and canonical IFN-I signaling were required for establishment of this innate immune memory and resulting augmented secondary antiviral responses. SARS-CoV-2-associated innate immune memory in alveolar macrophages was necessary and sufficient to ameliorate secondary disease caused by the heterologous respiratory pathogen influenza A virus. Insights into how innate immune memory shapes outcome of heterologous secondary diseases could facilitate the development of broadly effective therapeutic strategies.
2024-10-02 | GSE264679 | GEO
Project description:Drosophila immune priming to Enterococcus faecalis relies on immune tolerance rather than resistance
| PRJNA865019 | ENA
Project description:Helicobacter pylori is a widespread Gram-negative pathogen involved in a variety of gastrointestinal diseases, including gastritis, ulceration, mucosa-associated lymphoid tissue (MALT) lymphoma and gastric cancer. Immune responses aimed at eradication of H. pylori often prove futile, and paradoxically play a crucial role in the degeneration of epithelial integrity and disease progression. We have previously shown that H. pylori infection of primary human monocytes increases their potential to respond to subsequent bacterial stimuli – a process that may be involved in the generation of exaggerated, yet ineffective immune responses directed against the pathogen. In this study, we show that H. pylori-induced monocyte priming is not a common feature of Gram-negative bacteria, as Acinetobacter lwoffii induces tolerance to subsequent Escherichia coli lipopolysaccharide (LPS) challenge. Although the increased reactivity of H. pylori-infected monocytes seems to be specific to H. pylori, it appears to be independent of its virulence factors Cag pathogenicity island (CagPAI), cytotoxin associated gene A (CagA), vacuolating toxin A (VacA) and g-glutamyl transferase (g-GT). Utilizing whole-cell proteomics complemented with biochemical signaling studies, we show that H. pylori infection of monocytes induces a unique proteomic signature compared to other pro-inflammatory priming stimuli, namely LPS and the pathobiont A. lwoffii. Contrary to these tolerance- inducing stimuli, H. pylori priming leads to accumulation of NF-кB proteins, including p65/RelA, and thus to the acquisition of a monocyte phenotype more responsive to subsequent LPS challenge. The plasticity of pro-inflammatory responses based on abundance and availability of intracellular signaling molecules may be a heretofore underappreciated form of regulating innate immune memory as well as a novel facet of the pathobiology induced by H. pylori
2023-11-10 | PXD045072 | Pride