Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA296088 | ENA |
REPOSITORIES: ENA
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Project description:Viral vectors are attractive vaccine platforms that elicit robust innate and adaptive immune responses; however, viral vector vaccine candidates vary greatly in their ability to induce protective immunity. Ad5 vectors elicit robust CD8+ T cell responses but typically characterized by an exhausted phenotype. The mechanisms by which Ad5 vectors induce dysfunctional CD8+ T cells have not been fully elucidated. Here we demonstrate that Ad5 vectors, but not Ad26 vectors, elicit exhausted antigen-specific IL-10+PD1+ CD4+ T cells with a dysfunctional transcriptional profile, and these cells effectively suppress CD8+ T cells responses in vivo. Induction of inhibitory CD4+ T cells by Ad5 vectors was associated with increased IL-27 expression, and IL-27 blockade improved CD4+ T cell polyfunctionality. Together our data highlight a novel role for IL-27 in regulating responses to viral vector vaccines. Splenic CD45.2+ OT-II TCR-Tg CD4 T cells from CD45.1+ B6 mice immunized with Ad5-OVA or Ad26-OVA were purified by FACS on day 10 post-immunization
2016-06-01 | E-GEOD-73118 | biostudies-arrayexpress
Project description:Viral vectors are attractive vaccine platforms that elicit robust innate and adaptive immune responses; however, viral vector vaccine candidates vary greatly in their ability to induce protective immunity. Ad5 vectors elicit robust CD8+ T cell responses but typically characterized by an exhausted phenotype. The mechanisms by which Ad5 vectors induce dysfunctional CD8+ T cells have not been fully elucidated. Here we demonstrate that Ad5 vectors, but not Ad26 vectors, elicit exhausted antigen-specific IL-10+PD1+ CD4+ T cells with a dysfunctional transcriptional profile, and these cells effectively suppress CD8+ T cells responses in vivo. Induction of inhibitory CD4+ T cells by Ad5 vectors was associated with increased IL-27 expression, and IL-27 blockade improved CD4+ T cell polyfunctionality. Together our data highlight a novel role for IL-27 in regulating responses to viral vector vaccines.
2016-06-01 | GSE73118 | GEO
Project description:The inhibitory receptor Tim-3 has emerged as a critical regulator of the T cell dysfunction that develops in chronic viral infections and cancers. However, little is known regarding the signaling pathways that drive Tim-3 expression. Here, we demonstrate that IL-27 induces NFIL3, which promotes permissive chromatin remodeling of the Tim-3 locus and induces Tim-3 expression together with the immunosuppressive cytokine IL-10. We further show that the IL-27/NFIL3 signaling axis is crucial for the induction of Tim-3 in vivo. IL-27-conditioned Th1 cells exhibit reduced effector function and are poor mediators of intestinal inflammation. This inhibitory effect is NFIL3 dependent. In contrast, tumor-infiltrating lymphocytes (TILs) from IL-27R-/- mice exhibit reduced NFIL3, less Tim-3 expression and failure to develop dysfunctional phenotype, resulting in better tumor growth control. Thus, our data identify an IL-27/NFIL3 signaling axis as a key regulator of effector T cell responses via induction of Tim-3, IL-10, and T cell dysfunction. Through gene expression profile analysis, we identified a series of transcription factors that are induced by IL-27. Particularly, the induction of NFIL3 is highly relevant to Tim-3 expression. Naïve CD4+ T cells from C57BL/6 mice were stimulated with plate-bound anti-CD3 and anti-CD28 antibodies for 60 hours. The cells were subjected to gene profile analysis. A comparative transcriptome analysis between cells under neutral culture condition (Untreated) and cells treated with IL-27 (IL-27-treated) was peformed to screen transcription factors that are induced by IL-27 signaling.
2015-01-31 | E-GEOD-63628 | biostudies-arrayexpress
Project description:Malaria infection elicits both protective and pathogenic immune responses, and IL-27 is a critical cytokine that regulate effector responses during infection. Here, we identified a critical window of CD4+ T cell responses that is targeted by IL-27. Neutralization of IL-27 during acute infection with Plasmodium chabaudi expanded specific CD4+ T cells, which were maintained at high levels thereafter. In the chronic phase, Plasmodium-specific CD4+ T cells in IL-27-neutralized mice consisted mainly of CD127+KLRG1- and CD127-KLRG1+ subpopulations that displayed distinct cytokine production, proliferative capacity and are maintained in a manner independent of active infection. Single cell RNA-seq analysis revealed that these CD4+ T cell subsets formed independent clusters that express unique Th1-type genes. These IL-27-neutralized mice exhibited enhanced cellular and humoral immune responses and protection. These findings demonstrate that IL-27, which is produced during the acute phase of malaria infection, inhibits the development of unique Th1 memory precursor CD4+ T cells, suggesting potential implications for the development of vaccines and other strategic interventions.
2023-10-19 | GSE225556 | GEO
Project description:The inhibitory receptor Tim-3 has emerged as a critical regulator of the T cell dysfunction that develops in chronic viral infections and cancers. However, little is known regarding the signaling pathways that drive Tim-3 expression. Here, we demonstrate that IL-27 induces NFIL3, which promotes permissive chromatin remodeling of the Tim-3 locus and induces Tim-3 expression together with the immunosuppressive cytokine IL-10. We further show that the IL-27/NFIL3 signaling axis is crucial for the induction of Tim-3 in vivo. IL-27-conditioned Th1 cells exhibit reduced effector function and are poor mediators of intestinal inflammation. This inhibitory effect is NFIL3 dependent. In contrast, tumor-infiltrating lymphocytes (TILs) from IL-27R-/- mice exhibit reduced NFIL3, less Tim-3 expression and failure to develop dysfunctional phenotype, resulting in better tumor growth control. Thus, our data identify an IL-27/NFIL3 signaling axis as a key regulator of effector T cell responses via induction of Tim-3, IL-10, and T cell dysfunction. Through gene expression profile analysis, we identified a series of transcription factors that are induced by IL-27. Particularly, the induction of NFIL3 is highly relevant to Tim-3 expression.
2015-01-31 | GSE63628 | GEO
Project description:Interleukin (IL)-27 is a key immunosuppressive cytokine that counters T helper 17 (Th17) cell-mediated pathology. To identify mechanisms by which IL-27 might exert its immunosuppressive effect, we analyzed genes in T cells rapidly induced by IL-27. We found that IL-27 priming of naïve T cells upregulated expression of programmed death ligand 1 (PD-L1) in a signal transducer and activator of transcription (STAT)1-dependent manner. When co-cultured with naïve CD4+ T cells, IL-27-primed T cells inhibited the differentiation of Th17 cells in trans through a PD-1-PD-L1 interaction. In vivo, co-administration of naïve TCR transgenic T cells (2D2 T cells) with IL-27-primed T cells expressing PD-L1 inhibited the development of Th17 cells and protected from severe autoimmune encephalomyelitis. Thus, these data identify a suppressive activity of IL-27, by which CD4+ T cells can restrict differentiation of Th17 cells in trans. The roles of IL-6 and IL-27 in naïve CD4+ T cells was investigated by comparing global gene expression by Affymetrix Mouse Genome 430 2.0 Arrays. The functional outcome of STAT proteins was further evaluated by profiling gene expression changes between WT and STAT-deficient T cells in naïve CD4+ T cells with specific stimulation. All condition were done in biological triplicate.
2012-06-30 | E-GEOD-38375 | biostudies-arrayexpress
Project description:Immune responses to infection involve a careful balance: too weak a response allows pathogen replication; too strong risks immunopathology. The immunoregulatory cytokine IL-10 is a key factor in this balance, but the impact of IL-10 is context-dependent and current understanding of the factors that regulate IL-10 is incomplete. In this study, we demonstrated that the infection induced cytokine IL-27 promotes IL-10 expression in CD4+ T cells by directing epigenetic changes in H3K4me3, H3K27me3, H3K4me1 and H3K27Ac modifications at the Il10 locus. We showed that primary activation of antigen-specific CD4+ T cells, in the context of murine influenza infection, led to the long-term remodelling of the epigenetic landscape at both the Il10 promoter and a distinct active enhancer element ~ 25 kb upstream of the TSS. Intact IL-27 signalling was an essential requirement for these persistent epigenetic changes in memory CD4+ Tcells. We identified CREB1 as a transcription factor binding the Il10 active enhancer, and we showed that the ability of IL-27 to promote IL-10 expression was dependent on the histone acetyl transferase activity of the CREB1 complex member, p300. Together our data provide mechanistic insight into the action of IL-27 in regulating an immune response. We suggest that infection-induced cytokine signals direct epigenetic changes that moderate cytokine output in response to T cell receptor stimulation, regulating immune activity at sites of infection.
2022-12-31 | GSE135249 | GEO
Project description:Immune responses to infection involve a careful balance: too weak a response allows pathogen replication; too strong risks immunopathology. The immunoregulatory cytokine IL-10 is a key factor in this balance, but the impact of IL-10 is context-dependent and current understanding of the factors that regulate IL-10 is incomplete. In this study, we demonstrated that the infection induced cytokine IL-27 promotes IL-10 expression in CD4+ T cells by directing epigenetic changes in H3K4me3, H3K27me3, H3K4me1 and H3K27Ac modifications at the Il10 locus. We showed that primary activation of antigen-specific CD4+ T cells, in the context of murine influenza infection, led to the long-term remodelling of the epigenetic landscape at both the Il10 promoter and a distinct active enhancer element ~ 25 kb upstream of the TSS. Intact IL-27 signalling was an essential requirement for these persistent epigenetic changes in memory CD4+ Tcells. We identified CREB1 as a transcription factor binding the Il10 active enhancer, and we showed that the ability of IL-27 to promote IL-10 expression was dependent on the histone acetyl transferase activity of the CREB1 complex member, p300. Together our data provide mechanistic insight into the action of IL-27 in regulating an immune response. We suggest that infection-induced cytokine signals direct epigenetic changes that moderate cytokine output in response to T cell receptor stimulation, regulating immune activity at sites of infection.
2022-12-31 | GSE135247 | GEO
Project description:Viral infections are associated with extensive remodeling of the cellular proteome. Viruses encode gene products that manipulate host proteins to redirect cellular processes or subvert antiviral immune responses. One way in which host antiviral proteins antagonize viral infection is by associating with viral genomes and inhibiting essential viral processes. Adenovirus (AdV) encodes gene products from the early E4 region which are necessary for productive infection. Some cellular antiviral proteins are known to be targeted by AdV E4 gene products, resulting in their degradation or mislocalization. However, the full repertoire of host proteins manipulated by viral E4 proteins has not been defined. To identify cellular proteins and processes manipulated by viral products, we developed a global, un-biased proteomics approach to analyze changes to the host proteome during infection with Adenovirus serotype 5 (Ad5) virus. We combined quantification of total protein abundance in the proteome together with an analysis of proteins associated with viral genomes using isolation of Proteins on Nascent DNA (iPOND). By Integrating these proteomics datasets, we identified cellular factors that are degraded in an E4-dependent manner or are associated with the viral genome in the absence of E4 proteins. We further show that some identified proteins exert inhibitory effects on Ad5 infection. Our systems-level analysis reveals cellular processes that are manipulated during Ad5 infection and points to host factors counteracted by early viral proteins as they remodel the host proteome to promote efficient infection. Importance Viral infections stimulate myriad changes to the host cell proteome. As viruses harness cellular processes and counteract host defenses, they impact abundance, modifications, or localization of cellular proteins. Elucidating the dynamic changes to the cellular proteome during viral replication is integral to understanding how virus-host interactions influence the outcome of infection. Adenovirus serotype 5 (Ad5) encodes early gene products from the E4 genomic region that are known to alter host response pathways and promote replication, but the full extent of proteome modifications they mediate is not known. We use an integrated proteomics approach to quantitate protein abundance and protein associations with viral DNA during virus infection. Systems-level analysis identifies cellular proteins and processes impacted in an E4-dependent manner that could overcome potentially inhibitory host defenses. This study provides a global view of Adenovirus-mediated proteome remodeling which can serve as a model to investigate virus-host interactions of DNA viruses.
2021-08-11 | PXD025339 | Pride
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