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:T cells that encounter self-antigens after exiting the thymus avert autoimmunity through peripheral tolerance. Pathways for this include an unresponsive state known as anergy, clonal deletion, and T regulatory (Treg) cell induction. The transcription factor cues and kinetics that guide distinct peripheral tolerance outcomes remain unclear. Here, we found that anergic T cells are epigenetically primed for regulation by the non-classical AP-1 family member BATF. Tolerized BATF-deficient CD4+ T cells were resistant to anergy induction and instead underwent clonal deletion due to pro-apoptotic BIM (Bcl2l11) upregulation. During prolonged antigen exposure, BIM de-repression resulted in fewer PD-1+ conventional T cells as well as loss of peripherally-induced FOXP3+ Treg cells. Simultaneous Batf and Bcl2l11 knockdown meanwhile restored anergic T cell survival and Treg cell maintenance. The data identify the AP-1 nuclear factor BATF as a dominant driver of sustained T cell anergy and illustrate a mechanism for divergent peripheral tolerance fates.
2023-10-17 | GSE244278 | GEO
Project description:T cells that encounter self-antigens after exiting the thymus avert autoimmunity through peripheral tolerance. Pathways for this include an unresponsive state known as anergy, clonal deletion, and T regulatory (Treg) cell induction. The transcription factor cues and kinetics that guide distinct peripheral tolerance outcomes remain unclear. Here, we found that anergic T cells are epigenetically primed for regulation by the non-classical AP-1 family member BATF. Tolerized BATF-deficient CD4+ T cells were resistant to anergy induction and instead underwent clonal deletion due to pro-apoptotic BIM (Bcl2l11) upregulation. During prolonged antigen exposure, BIM de-repression resulted in fewer PD-1+ conventional T cells as well as loss of peripherally-induced FOXP3+ Treg cells. Simultaneous Batf and Bcl2l11 knockdown meanwhile restored anergic T cell survival and Treg cell maintenance. The data identify the AP-1 nuclear factor BATF as a dominant driver of sustained T cell anergy and illustrate a mechanism for divergent peripheral tolerance fates.
2023-10-17 | GSE244276 | GEO
Project description:Drug resistance and tolerance eliminate the therapeutic potential of antibiotics against pathogens. Antibiotic tolerance by bacterial biofilms often leads to persistent infections, but its mechanisms are unclear. To uncover antibiotic tolerance mechanisms in biofilms, we applied stable isotope labeling with amino acids (SILAC) proteomics to selectively label and compare proteomes of sensitive and tolerant subpopulations of biofilms formed by Pseudomonas aeruginosa towards colistin, a 'last-resort' antibiotic against multidrug-resistant Gram-negative pathogens. Migration was essential in forming colistin-tolerant biofilm subpopulations, as colistin-tolerant cell-aggregates migrated with type IV pili, onto the top of killed biofilm. The colistin-tolerant cell-aggregates employed quorum sensing (QS) to initiate the formation of fresh colistin-tolerant subpopulations, highlighting multicellular behavior in antibiotic tolerance development. Erythromycin treatment which inhibits motility and QS, boosted biofilm eradication by colistin. This novel ‘-omics’ strategy to study antibiotic tolerant cells provides key insights for designing novel treatments against infections unsuppressed by conventional antimicrobials.
2016-02-16 | PXD002369 | Pride
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:The inflammatory response initiated by microbial products signaling through Toll-like receptors (TLRs) of the innate immune system is essential for host defense against infection. Because inflammation can be harmful to host tissues, the innate response is highly regulated. Negative regulation of TLR4, the receptor for bacterial lipopolysaccharide (LPS), results in LPS tolerance, defined as hyporesponsiveness to repeated stimulation with LPS. LPS tolerance is thought to protect the host from excessive inflammation by turning off TLR4 signal, which then shuts down TLR-induced genes. However, TLR signaling induces hundreds of genes with very different functions. We reasoned that genes with different functions should have different requirements for regulation. Specifically, genes encoding proinflammatory mediators should be transiently inactivated to limit tissue damage, while genes encoding antimicrobial effectors, which directly target pathogens, should remain inducible in tolerant cells to protect the host from infection. Using an in vitro system of LPS tolerance in macrophages, here we show that TLR-induced genes may indeed be divided into two distinct categories based on their functions and regulatory requirements. Further, we show these distinct groups are regulated by gene-specific, and not signal-specific mechanisms. Experiment Overall Design: We examined gene expression using affymetrix genechips in 3 groups of murine bone-marrow derived macrophages: Naive (untreated), Naive stimulated with LPS, and Tolerant stimulated with LPS. Two biological replicates were performed for each group.
2008-06-15 | E-GEOD-7348 | biostudies-arrayexpress
Project description:Investigating the epigenetic and transciptional changes induced in tolerant T cells
| PRJNA613647 | ENA