Gene expression profiling of sarcoma T cells deriving from Csf3r WT and KO mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE109031 | GEO | 2019/06/24
REPOSITORIES: GEO
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Project description:This a model from the article:
Sequential polarization and imprinting of type 1 T helper lymphocytes by interferon-gamma and interleukin-12.
Schulz EG, Mariani L, Radbruch A, Höfer T.
Immunity.2009;30(5):666-8.
19409816,
Abstract:
Differentiation of naive T lymphocytes into type I T helper (Th1) cells requires interferon-gamma and interleukin-12. It is puzzling that interferon-gamma induces the Th1 transcription factor T-bet, whereas interleukin-12 mediates Th1 cell lineage differentiation. We use mathematical modeling to analyze the expression kinetics of T-bet, interferon-gamma, and the IL-12 receptor beta2 chain (IL-12Rbeta2) during Th1 cell differentiation, in the presence or absence of interleukin-12 or interferon-gamma signaling. We show that interferon-gamma induced initial T-bet expression, whereas IL-12Rbeta2 was repressed by T cell receptor (TCR) signaling. The termination of TCR signaling permitted upregulation of IL-12Rbeta2 by T-bet and interleukin-12 signaling that maintained T-bet expression. This late expression of T-bet, accompanied by the upregulation of the transcription factors Runx3 and Hlx, was required to imprint the Th cell for interferon-gamma re-expression. Thus initial polarization and subsequent imprinting of Th1 cells are mediated by interlinked, sequentially acting positive feedback loops of TCR-interferon-gamma-Stat1-T-bet and interleukin-12-Stat4-T-bet signaling.
The original model was created by:
Edda G. Schulz
schulz@drfz.de
Theoretical Biophysics, Institute of Biology, Humboldt Universität, Invalidenstrasse 42, 10115 Berlin, Germany.
This model originates from BioModels Database: A Database of Annotated Published Models. It is copyright (c) 2005-2009 The BioModels Team.For more information see the terms of use.To cite BioModels Database, please use Le Novère N., Bornstein B., Broicher A., Courtot M., Donizelli M., Dharuri H., Li L., Sauro H., Schilstra M., Shapiro B., Snoep J.L., Hucka M. (2006) BioModels Database: A Free, Centralized Database of Curated, Published, Quantitative Kinetic Models of Biochemical and Cellular Systems Nucleic Acids Res., 34: D689-D691.
2009-06-10 | BIOMD0000000215 | BioModels
Project description:Given T-bet is a master regulator for Th1 differentiation that produce IFN-gamma, underlining mechanisms accounted for the distinct GVHD outcomes caused by T-bet- versus IFN-gamma-deficient donor T cells are unclear. We hypothesize that GVHD is regulated by T-bet-dependent but IFN-gamma-independent molecules. To identify these molecules, we isolated donor T cells from spleen cells of the recipients that were transplanted with WT, T-bet-/- or IFN-gamma-/- CD4 T cells for 7 days. The gene profile of isolated T cells was measured by microarray analysis using GeneChip Mouse Genome 430 2.0 arrays (Affymetrix) according to the manufacturerM-^Rs instructions. Array images were analyzed and processed by robust multi-array average (RMA) procedure.
2014-10-30 | E-MTAB-2198 | biostudies-arrayexpress
Project description:Interferon-gamma (IFN-gamma) is approved as a drug to treat chronic granulomatous disease and osteopetrosis and is also used in hyperimmunoglobulin E syndromes. These primary immunodeficiencies involve defects in neutrophils/polymorphonuclear cells. Neutrophils mature in the bone marrow and then enter the blood where they quickly undergo apoptotic cell death with a half-life of 5-10 hours. Therefore we reasoned that IFN-gamma might exert its effects on neutrophils via prolonged exposure to cells undergoing maturation toward a terminally differentiated state in the marrow rather than by its brief exposure to short-lived circulating cells. To explore this possibility we made use of PLB-985 cells which are a myeloblast-like myeloid cell line that can be differentiated into a mature, neutrophil-like state by treatment with various agents including DMSO. In initial studies we investigated transcription and protein expression in PLB-985 cells undergoing DMSO-mediated maturation in the presence or absence of IFN-gamma and identified several classes of immunity related genes that were differentially expressed in the presence of the drug and could potentially explain the immune supportive properties of IFN-gamma. Next we explored if the effect of IFN-gamma on expression of these genes is dependent on whether the cells are undergoing maturation; to do this we compared the effects of IFN-gamma on cells cultured with and without DMSO. For a subset of genes the expression level changes caused by IFN-gamma were much greater in maturing cells than non-maturing cells. These findings indicate that developmental changes associated with cell maturation can modulate the effects of IFN-gamma and supports our hypothesis that the effects of the drug on developing neutrophils in the bone marrow may be very different from its effects on mature cells in the blood. We also compared the effects on gene expression of applying IFN-gamma either during DMSO mediated PLB-985 cell maturation or after maturation i.e. IFN-gamma was applied to already mature cells. For some genes we found that IFN-gamma applied to mature cells caused large changes in expression similar to those seen when IFN-gamma was applied during maturation, however for other genes no effect was seen when drug was applied to mature cells but large effects were seen when drug was applied during DMSO treatment. This data suggests that, in the former class of genes, the effects of IFN-gamma application during maturation are largely the result of the effects of the drug on cells approaching full maturity but in the latter class of genes the effects of IFN-gamma only become apparent when it is present throughout maturation. This further supports our hypothesis that the effects of IFN-gamma are modulated by developmental changes associated with cell maturation.
2017-08-31 | E-MTAB-5690 | biostudies-arrayexpress
Project description:Extracellular cold-inducible RNA-binding protein (eCIRP) is a key mediator of severity and mortality in sepsis. We found that stimulation of mouse bone marrow–derived neutrophils (BMDNs) with eCIRP generated a distinct neutrophil subpopulation, characterized by cell surface markers of both antigen-presenting cells and aged neutrophils as well as expression of IL-12, which we named antigen-presenting aged neutrophils (APANs). The frequency of APANs was significantly increased in the blood, spleen, and lungs of WT mice subjected to cecal ligation and puncture–induced sepsis but not in CIRP–/– mice. Patients with sepsis had a significant increase in circulating APAN counts compared with healthy individuals. Compared with non–APAN-transferred mice, APAN-transferred septic mice had increased serum levels of injury and inflammatory markers, exacerbated acute lung injury (ALI), and worsened survival. APANs and CD4+ T cells colocalized in the spleen, suggesting an immune interaction between these cells. APANs cocultured with CD4+ T cells significantly induced the release of IFN-γ via IL-12. BMDNs stimulated with eCIRP and IFN-γ underwent hyper-NETosis. Stimulating human peripheral blood neutrophils with eCIRP also induced APANs, and stimulating human neutrophils with eCIRP and IFN-γ caused hyper-NETosis. Thus, eCIRP released during sepsis induced APANs to aggravate ALI and worsen the survival of septic animals via CD4+ T cell activation, Th1 polarization, and IFN-γ–mediated hyper-NETosis.
2023-09-27 | GSE228482 | GEO
Project description:Host defense requires the specification of CD4+ helper T (Th) cells into distinct fates including Th1 cells that preferentially produce interferon γ(IFN-γ ).IFN-γ , a member of a large family of anti-pathogenic and anti-tumor IFNs, induces T-bet, a lineage defining transcription factor for Th1 cells, which in turn supports IFN-γ production in a feed-forward manner. Herein, we show a cell intrinsic role of T- bet to influence how T cells perceive their secreted product in the environment. In the absence of T-bet, IFN-γ aberrantly induces a type I IFN transcriptomic program. T-bet preferentially represses genes and pathways ordinarily activated by type I IFNs to ensure that its transcriptional response does not evoke an aberrant amplification of type I IFN signaling circuitry otherwise triggered by its own product.
2017-06-12 | GSE96724 | GEO
Project description:Macrophages are known to be polarized into inflammatory (M1) and immunoregulatory (M2) cells when they are stimulated by agonists such as IFN-gamma and IL-4, respectively. If circulating monocytes may be polarized in response to T cell signals is often misguidedly deduced from macrophage results. Here the transcriptional responses of human CD14+ monocytes to IFN-gamma and IL-4 were analyzed using whole genome microarrays. A principal component analysis and hierarchical clustering showed that monocyte and macrophage responses were distinct. Monocytes stimulated with IFN-gamma and IL-4 for 6 hours exhibited some features of macrophage polarization. Indeed, when 80 genes considered as M1 and M2 genes were analyzed, we found that M1 genes were modulated in response to IFN-gamma and that M2 genes were modulated in response to IL-4. The M1 polarization of monocytes was transient because only M2 genes were modulated when monocytes were stimulated with IFN-gamma and IL-4 for 18 hours. However, the activation of monocytes by IFN-gamma and IL-4 could not be reduced to M1/M2 polarization status. Indeed, monocytes exhibited early specific signatures composed of 46 and 39 up-regulated genes in response to IFN-gamma and IL-4, respectively, and a late signature common to both molecules that consisted of 57 up-regulated genes. Taken together, these results demonstrated the extreme plasticity of human monocytes and suggested the existence of a core transcriptional termination program. Using early and late signatures might be pertinent to investigate monocyte activation in inflammatory or infectious diseases. Monocytes were stimulated with IFN-gamma (20ng/mL) or IL-4 (20ng/mL) for 6 and 18 hours or culture for 6 and 18 hours without agonist (Unstimulated samples). Monocytes-derived-macrophages (MDM) stimulated with IFN-gamma and IL-4 for 18 hours were used as controls. Each microarray is derived from a single biological sample.
2013-03-15 | E-GEOD-36537 | biostudies-arrayexpress
Project description:Complete polarization of macrophages towards an M1-like proinflammatory and antimicrobial state requires combined action of IFN-γ and LPS. Synergistic activation of canonical inflammatory NF-κB target genes by IFN-γ and LPS is well appreciated, but less is known about whether IFN-γ negatively regulates components of the LPS response, and how this affects polarization. A combined transcriptomic and epigenomic approach revealed that IFN-γ selectively abrogates LPS-induced feedback and select metabolic pathways by suppressing TLR4-mediated activation of gene enhancers. In contrast to superinduction of inflammatory genes via enhancers that harbor IRF sequences and bind STAT1, IFN-γ-mediated repression targeted enhancers with STAT sequences that bound STAT3. TLR4-activated IFN-γ-suppressed enhancers comprised two subsets distinguished by differential regulation of histone acetylation and recruitment of STAT3, CDK8 and cohesin, and were functionally inactivated by IFN-γ. These findings reveal that IFN-γ suppresses feedback inhibitory and metabolic components of the TLR response to achieve full M1 polarization, and provide insights into mechanisms by which IFN-γ selectively inhibits TLR4-induced transcription.
2019-06-12 | GSE120942 | GEO
Project description:Complete polarization of macrophages towards an M1-like proinflammatory and antimicrobial state requires combined action of IFN-γ and LPS. Synergistic activation of canonical inflammatory NF-κB target genes by IFN-γ and LPS is well appreciated, but less is known about whether IFN-γ negatively regulates components of the LPS response, and how this affects polarization. A combined transcriptomic and epigenomic approach revealed that IFN-γ selectively abrogates LPS-induced feedback and select metabolic pathways by suppressing TLR4-mediated activation of gene enhancers. In contrast to superinduction of inflammatory genes via enhancers that harbor IRF sequences and bind STAT1, IFN-γ-mediated repression targeted enhancers with STAT sequences that bound STAT3. TLR4-activated IFN-γ-suppressed enhancers comprised two subsets distinguished by differential regulation of histone acetylation and recruitment of STAT3, CDK8 and cohesin, and were functionally inactivated by IFN-γ. These findings reveal that IFN-γ suppresses feedback inhibitory and metabolic components of the TLR response to achieve full M1 polarization, and provide insights into mechanisms by which IFN-γ selectively inhibits TLR4-induced transcription.
2019-06-20 | GSE130567 | GEO
Project description:Complete polarization of macrophages towards an M1-like proinflammatory and antimicrobial state requires combined action of IFN-γ and LPS. Synergistic activation of canonical inflammatory NF-κB target genes by IFN-γ and LPS is well appreciated, but less is known about whether IFN-γ negatively regulates components of the LPS response, and how this affects polarization. A combined transcriptomic and epigenomic approach revealed that IFN-γ selectively abrogates LPS-induced feedback and select metabolic pathways by suppressing TLR4-mediated activation of gene enhancers. In contrast to superinduction of inflammatory genes via enhancers that harbor IRF sequences and bind STAT1, IFN-γ-mediated repression targeted enhancers with STAT sequences that bound STAT3. TLR4-activated IFN-γ-suppressed enhancers comprised two subsets distinguished by differential regulation of histone acetylation and recruitment of STAT3, CDK8 and cohesin, and were functionally inactivated by IFN-γ. These findings reveal that IFN-γ suppresses feedback inhibitory and metabolic components of the TLR response to achieve full M1 polarization, and provide insights into mechanisms by which IFN-γ selectively inhibits TLR4-induced transcription.
2019-06-12 | GSE120944 | GEO
Project description:Complete polarization of macrophages towards an M1-like proinflammatory and antimicrobial state requires combined action of IFN-γ and LPS. Synergistic activation of canonical inflammatory NF-κB target genes by IFN-γ and LPS is well appreciated, but less is known about whether IFN-γ negatively regulates components of the LPS response, and how this affects polarization. A combined transcriptomic and epigenomic approach revealed that IFN-γ selectively abrogates LPS-induced feedback and select metabolic pathways by suppressing TLR4-mediated activation of gene enhancers. In contrast to superinduction of inflammatory genes via enhancers that harbor IRF sequences and bind STAT1, IFN-γ-mediated repression targeted enhancers with STAT sequences that bound STAT3. TLR4-activated IFN-γ-suppressed enhancers comprised two subsets distinguished by differential regulation of histone acetylation and recruitment of STAT3, CDK8 and cohesin, and were functionally inactivated by IFN-γ. These findings reveal that IFN-γ suppresses feedback inhibitory and metabolic components of the TLR response to achieve full M1 polarization, and provide insights into mechanisms by which IFN-γ selectively inhibits TLR4-induced transcription.
2019-06-12 | GSE120943 | GEO