T cell intrinsic STAT1 signaling prevents aberrant Th1 responses during acute toxoplasmosis
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE236970 | GEO | 2023/07/10
REPOSITORIES: GEO
Similar Datasets
Project description:IL-27 is a potent antagonist of TH1-mediated inflammation, but the basis for this effect is not fully understood. Recent studies identified a population of T-bet+ CXCR3+ Treg that limit TH1-mediated immune pathology. The studies presented here demonstrate that IL-27-mediated STAT1 activation promotes Treg expression of T-bet and CXCR3. Infection with Toxoplasma gondii induced a similar Treg population that limits T cell responses and this population at mucosal sites is IL-27-dependent. Furthermore, transfer of Treg ameliorated the infection-induced CD4+ T cell-mediated pathology observed in IL-27p28-/- mice. Although IFN-γ promoted a similar population of cells in the periphery, it did not compensate for the absence of IL-27 at mucosal sites and microarray analysis revealed that Treg exposed to either cytokine have distinct transcriptional profiles. These findings suggest that IFN-γ and IL-27 have different roles in Treg biology but define IL-27 as a key cytokine that promotes the development of Treg specialized to control TH1 immunity. Three conditions were analyzed across two timepoints. Inducible regulatory T cells (iTreg) were generated in vitro in the presence of IL-27, IFNg or under 'Neutral' conditions as a control. Samples were collected at 10 hours and 2 days during the culture period. Three biological replicates were used for each condition.
2012-09-07 | E-GEOD-38686 | biostudies-arrayexpress
Project description:Interleukin-21 (IL-21) is a type 1 cytokine essential for immune cell differentiation and function. Although IL-21 can activate several STAT family transcription factors, previous studies focused mainly on the role of STAT3 in IL-21 signaling. Here, we investigated the role of STAT1 and show that STAT1 and STAT3 have at least partially opposing roles in IL-21 signaling in CD4+ T cells. IL-21 induced STAT1 phosphorylation, and this was augmented in Stat3-deficient CD4+ T cells. RNA-Seq analysis of CD4+ T cells from Stat1- and Stat3-deficient mice revealed that both STAT1 and STAT3 are critical for IL-21-mediated gene regulation. Expression of some genes, including Tbx21 and Ifng, was differentially regulated by STAT1 and STAT3, and interestingly, ChIP-Seq analysis showed that STAT3 binding at Tbx21 and Ifng loci was attenuated in Stat1-deficient cells. Moreover, opposing actions of STAT1 and STAT3 on IFN- expression in CD4+ T cells were demonstrated in vivo during chronic lymphocytic choriomeningitis (LCMV) infection. Finally, IL-21-mediated induction of STAT1 phosphorylation, as well as IFNG and TBX21 expression, were higher in CD4+ T cells from patients with autosomal dominant hyper-IgE syndrome (AD-HIES), which is caused by STAT3 deficiency. These data indicate an interplay between STAT1 and STAT3 in fine-tuning IL-21 actions. Genome-wide transcription factors mapping and binding of STAT3 in mouse CD4+ T cells in both WT and Stat1-deficient mice. RNA-Seq is performed in mouse CD4+ T cells in WT, Stat1-deficient and Stat3-deficient mice.
2015-07-01 | E-GEOD-63204 | biostudies-arrayexpress
Project description:IL-27 is a potent antagonist of TH1-mediated inflammation, but the basis for this effect is not fully understood. Recent studies identified a population of T-bet+ CXCR3+ Treg that limit TH1-mediated immune pathology. The studies presented here demonstrate that IL-27-mediated STAT1 activation promotes Treg expression of T-bet and CXCR3. Infection with Toxoplasma gondii induced a similar Treg population that limits T cell responses and this population at mucosal sites is IL-27-dependent. Furthermore, transfer of Treg ameliorated the infection-induced CD4+ T cell-mediated pathology observed in IL-27p28-/- mice. Although IFN-γ promoted a similar population of cells in the periphery, it did not compensate for the absence of IL-27 at mucosal sites and microarray analysis revealed that Treg exposed to either cytokine have distinct transcriptional profiles. These findings suggest that IFN-γ and IL-27 have different roles in Treg biology but define IL-27 as a key cytokine that promotes the development of Treg specialized to control TH1 immunity.
2012-09-07 | GSE38686 | GEO
Project description:Interleukin-27 (IL27) is a type-I-cytokine of the IL6/IL12 family predominantly secreted by activated macrophages and dendritic cells. Best understood are the effects of IL27 on immune cells where it has been described to have pro- or anti-inflammatory properties, either promoting TH1 responses or suppressing TH1 and TH2 responses. The action on other cell types is less well studied. In the liver, IL27 expression was observed to be upregulated in patients with hepatitis B, and sera of hepatocellular carcinoma (HCC) patients contain significantly elevated levels of IL27 compared to healthy controls or patients with hepatitis and/or liver cirrhosis. We previously reported interferon-gamma-like antiviral activity of IL27 in hepatic cells. Here we further studied the effects of IL27 on HCC cells in comparison to other cytokines. We were especially interested in the relevance of the IL27-induced STAT3 activation. Thus we compared its response with those induced by IFNg (STAT1-dominated response) or IL6-type cytokines (IL6, Hyper-IL6 or OSM) (STAT3-dominated response). We find that in hepatocytes, IL27 induces an IFNg-like, STAT1-dependent transcriptional response, but we do not find an effective STAT3-dependent response. The availability of STAT1 seems critical in the shaping of the IL27 response, as the siRNA knock-down of STAT1 revealed its ability to induce the acute-phase protein gamma-fibrinogen, a typical IL6 family characteristic. Moreover, we describe a crosstalk between the signaling of IL6-type cytokines and IL27: responses to the gp130-engaging cytokine IL27 (but not those to IFNs) can be inhibited by IL6-type cytokine pre-stimulation, likely by a SOCS3-mediated mechanism. This experiment represents microarray analysis of three hepatocellular carcinoma cell lines treated with IL-27, IFNg, hyper-IL6 or OSM in combination with shRNA knockdown of STAT3.
2017-07-05 | E-MTAB-4570 | biostudies-arrayexpress
Project description:Interleukin-21 (IL-21) is a type 1 cytokine essential for immune cell differentiation and function. Although IL-21 can activate several STAT family transcription factors, previous studies focused mainly on the role of STAT3 in IL-21 signaling. Here, we investigated the role of STAT1 and show that STAT1 and STAT3 have at least partially opposing roles in IL-21 signaling in CD4+ T cells. IL-21 induced STAT1 phosphorylation, and this was augmented in Stat3-deficient CD4+ T cells. RNA-Seq analysis of CD4+ T cells from Stat1- and Stat3-deficient mice revealed that both STAT1 and STAT3 are critical for IL-21-mediated gene regulation. Expression of some genes, including Tbx21 and Ifng, was differentially regulated by STAT1 and STAT3, and interestingly, ChIP-Seq analysis showed that STAT3 binding at Tbx21 and Ifng loci was attenuated in Stat1-deficient cells. Moreover, opposing actions of STAT1 and STAT3 on IFN- expression in CD4+ T cells were demonstrated in vivo during chronic lymphocytic choriomeningitis (LCMV) infection. Finally, IL-21-mediated induction of STAT1 phosphorylation, as well as IFNG and TBX21 expression, were higher in CD4+ T cells from patients with autosomal dominant hyper-IgE syndrome (AD-HIES), which is caused by STAT3 deficiency. These data indicate an interplay between STAT1 and STAT3 in fine-tuning IL-21 actions.
2015-07-01 | GSE63204 | GEO
Project description:Qi2013 - IL-6 and IFN crosstalk model
This model
[BIOMD0000000544]
describes the crosstalk between IFN-gamma and IL-6 induced
signalling; it aims to outline mechanisms and factors that may
control the interaction between both signalling pathways,
discussing a role of heterodimer formation in signalling
dysfunction.
To account for the possibility of different IFNR and gp130
binding sites for STAT1 and STAT3, model 1
[BIOMD0000000543]
assumes that there is no competition between STAT1 and STAT3 for
the receptor complexes (includes two extra reactions).
The reverse of this is true in model 2
[BIOMD0000000544]
where it generally is assumed that there is competition between
STAT1 and STAT3 for the receptor complexes.
This model is described in the article:
Elucidating the crosstalk
mechanism between IFN-gamma and IL-6 via mathematical
modelling.
Qi YF, Huang YX, Wang HY, Zhang Y,
Bao YL, Sun LG, Wu Y, Yu CL, Song ZB, Zheng LH, Sun Y, Wang GN,
Li YX.
BMC Bioinformatics 2013; 14: 41
Abstract:
BACKGROUND: Interferon-gamma (IFN-gamma) and interleukin-6
(IL-6) are multifunctional cytokines that regulate immune
responses, cell proliferation, and tumour development and
progression, which frequently have functionally opposing roles.
The cellular responses to both cytokines are activated via the
Janus kinase/signal transducer and activator of transcription
(JAK/STAT) pathway. During the past 10 years, the crosstalk
mechanism between the IFN-gamma and IL-6 pathways has been
studied widely and several biological hypotheses have been
proposed, but the kinetics and detailed crosstalk mechanism
remain unclear. RESULTS: Using established mathematical models
and new experimental observations of the crosstalk between the
IFN-gamma and IL-6 pathways, we constructed a new crosstalk
model that considers three possible crosstalk levels: (1) the
competition between STAT1 and STAT3 for common receptor docking
sites; (2) the mutual negative regulation between SOCS1 and
SOCS3; and (3) the negative regulatory effects of the formation
of STAT1/3 heterodimers. A number of simulations were tested to
explore the consequences of cross-regulation between the two
pathways. The simulation results agreed well with the
experimental data, thereby demonstrating the effectiveness and
correctness of the model. CONCLUSION: In this study, we
developed a crosstalk model of the IFN-gamma and IL-6 pathways
to theoretically investigate their cross-regulation mechanism.
The simulation experiments showed the importance of the three
crosstalk levels between the two pathways. In particular, the
unbalanced competition between STAT1 and STAT3 for IFNR and
gp130 led to preferential activation of IFN-gamma and IL-6,
while at the same time the formation of STAT1/3 heterodimers
enhanced preferential signal transduction by sequestering a
fraction of the activated STATs. The model provided a good
explanation of the experimental observations and provided
insights that may inform further research to facilitate a
better understanding of the cross-regulation mechanism between
the two pathways.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000544.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000544 | BioModels
Project description:Qi2013 - IL-6 and IFN crosstalk model
(non-competitive)
This model
[BIOMD0000000543]
describes the crosstalk between IFN-gamma and IL-6 induced
signalling; it aims to outline mechanisms and factors that may
control the interaction between both signalling pathways,
discussing a role of heterodimer formation in signalling
dysfunction.
To account for the possibility of different IFNR and gp130
binding sites for STAT1 and STAT3, model 1
[BIOMD0000000543]
assumes that there is no competition between STAT1 and STAT3 for
the receptor complexes (includes two extra reactions).
The reverse of this is true in model 2
[BIOMD0000000544]
where it generally is assumed that there is competition between
STAT1 and STAT3 for the receptor complexes.
This model is described in the article:
Elucidating the crosstalk
mechanism between IFN-gamma and IL-6 via mathematical
modelling.
Qi YF, Huang YX, Wang HY, Zhang Y,
Bao YL, Sun LG, Wu Y, Yu CL, Song ZB, Zheng LH, Sun Y, Wang GN,
Li YX.
BMC Bioinformatics 2013; 14: 41
Abstract:
BACKGROUND: Interferon-gamma (IFN-gamma) and interleukin-6
(IL-6) are multifunctional cytokines that regulate immune
responses, cell proliferation, and tumour development and
progression, which frequently have functionally opposing roles.
The cellular responses to both cytokines are activated via the
Janus kinase/signal transducer and activator of transcription
(JAK/STAT) pathway. During the past 10 years, the crosstalk
mechanism between the IFN-gamma and IL-6 pathways has been
studied widely and several biological hypotheses have been
proposed, but the kinetics and detailed crosstalk mechanism
remain unclear. RESULTS: Using established mathematical models
and new experimental observations of the crosstalk between the
IFN-gamma and IL-6 pathways, we constructed a new crosstalk
model that considers three possible crosstalk levels: (1) the
competition between STAT1 and STAT3 for common receptor docking
sites; (2) the mutual negative regulation between SOCS1 and
SOCS3; and (3) the negative regulatory effects of the formation
of STAT1/3 heterodimers. A number of simulations were tested to
explore the consequences of cross-regulation between the two
pathways. The simulation results agreed well with the
experimental data, thereby demonstrating the effectiveness and
correctness of the model. CONCLUSION: In this study, we
developed a crosstalk model of the IFN-gamma and IL-6 pathways
to theoretically investigate their cross-regulation mechanism.
The simulation experiments showed the importance of the three
crosstalk levels between the two pathways. In particular, the
unbalanced competition between STAT1 and STAT3 for IFNR and
gp130 led to preferential activation of IFN-gamma and IL-6,
while at the same time the formation of STAT1/3 heterodimers
enhanced preferential signal transduction by sequestering a
fraction of the activated STATs. The model provided a good
explanation of the experimental observations and provided
insights that may inform further research to facilitate a
better understanding of the cross-regulation mechanism between
the two pathways.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000543.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000543 | BioModels
Project description:IL-27 has been shown to play a role in modulating functions of diverse cell types like Th1, Th2, NK and B cells demonstrating both pro and anti-inflammatory roles. It is also capable of inducing STAT1, STAT3 and ISG's. To investigate the role of IL-27 on hepatocytes, Huh7.5 cells were treated with Il-27 and analysed the differentially expressed genes by microarray analysis. Microarray analysis showed that the upregulated genes belonged to antigen presentation and DNA replication pathways and involved strong upregulation of CXCL-10 a gene associated with liver inflammation.
2016-11-09 | GSE89610 | GEO
Project description:The death receptor Fas removes activated lymphocytes through apoptosis. Previous transcriptional profiling predicted that Fas positively regulates interleukin (IL)-17-producing T helper (Th17) cells. We here demonstrate that Fas promoted the generation and stability of Th17 cells and prevented their differentiation into Th1 cells. Mice with T cell- and Th17 cell-specific deletion of Fas were protected from induced autoimmunity and Th17 cell differentiation and stability was impaired. Fas deficient Th17 cells instead developed a Th1 cell-like transcriptional profile, which we predicted by a new algorithm to depend on STAT1. Experimentally, Fas indeed bound and sequestered STAT1 and Fas deficiency enhanced IL-6 induced STAT1 activation and nuclear translocation, whereas Fas-STAT1 double-deficiency reversed the transcriptional changes induced by Fas deficiency. Thus, our computational and experimental approach identified Fas as a regulator of the Th17-to-Th1 cell balance by controlling the availability of the opposing STAT1 and STAT3 proteins with direct impact on autoimmunity.
2018-03-10 | GSE111244 | GEO
Project description:IL-6 and IL-27 have antagonistic and overlapping functions, signal through a shared receptor subunit and employ the same downstream STAT proteins. To evaluate the degree of specificity and redundancy for these cytokines, we quantified global transcriptomic changes induced by the two cytokines and determined the relative contributions of STAT1 and STAT3 using genetic models and ChIP-seq. We found a high degree of overlap of the transcriptomes induced by IL-6 and IL-27 and extremely few examples in which the cytokines acted in opposition. Using STAT deficient cells and T cells from patients with gain-of-function STAT1 mutations, we show that STAT3 was responsible for the overall transcriptional output driven by both cytokines, whereas STAT1 was the driver of cytokine specificity. STAT1 did not compensate for the lack STAT3; on the contrary, much of STAT1 binding to chromatin was STAT3 dependent. Thus, STAT1 shapes the specific cytokine signature superimposed upon STAT3’s action. Integrated analysis of transcriptome and transcription factor binding data from cytokine treated CD4+T cells
2015-05-27 | E-GEOD-65621 | biostudies-arrayexpress