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The transcription factor IRF2 drives interferon-mediated CD8+ T cell exhaustion to restrict anti-tumor immunity

ABSTRACT: The transcription factor IRF2 drives interferon-mediated CD8+ T cell exhaustion to restrict anti-tumor immunity

PROVIDER: PRJNA818703 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18435411_1.fastq.gz	Fastqsanger.gz
	SRR18435411_2.fastq.gz	Fastqsanger.gz
	SRR18435412_1.fastq.gz	Fastqsanger.gz
	SRR18435412_2.fastq.gz	Fastqsanger.gz
	SRR21834911_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

The transcription factor IRF2 drives interferon-mediated CD8+ T cell exhaustion to restrict anti-tumor immunity

Project description:Type I Interferons (IFN-I) stimulate pro-inflammatory programs critical for immune activation, but also induce immune-suppressive feedback circuits that contribute to the failure of cancer control. Yet, how IFN-Is differentially induce these opposing programs remains enigmatic. We establish that the transcription factor Interferon Regulatory Factor 2 (IRF2) is a central feedback molecule attenuating IFN signaling and driving CD8 T cell exhaustion in the tumor microenvironment. IRF2 inhibits CD8 T cell effector function in response to sustained interferon signaling by programming T cell exhaustion. Lineage-specific deletion of IRF2 limits CD8 T cells exhaustion to maintain effector functions, thereby enabling long-term tumor control, and increased responsiveness to immune-checkpoint and adoptive cell therapies. Long-term tumor control by IRF2-deficient CD8 T cells is dependent on continuous integration of both IFN-I and IFN? signals, which in the absence of IRF2, potentiate sustained effector function instead of exhaustion. Thus, IRF2 redirects IFN signalling to drive T cell exhaustion and prevent tumor control.

2022-11-10 | GSE199177 | GEO

The transcription factor IRF2 drives interferon-mediated CD8<sup>+</sup> T cell exhaustion to restrict anti-tumor immunity.

Project description:Type I and II interferons (IFNs) stimulate pro-inflammatory programs that are critical for immune activation, but also induce immune-suppressive feedback circuits that impede control of cancer growth. Here, we sought to determine how these opposing programs are differentially induced. We demonstrated that the transcription factor interferon regulatory factor 2 (IRF2) was expressed by many immune cells in the tumor in response to sustained IFN signaling. CD8+ T cell-specific deletion of IRF2 prevented acquisition of the T cell exhaustion program within the tumor and instead enabled sustained effector functions that promoted long-term tumor control and increased responsiveness to immune checkpoint and adoptive cell therapies. The long-term tumor control by IRF2-deficient CD8+ T cells required continuous integration of both IFN-I and IFN-II signals. Thus, IRF2 is a foundational feedback molecule that redirects IFN signals to suppress T cell responses and represents a potential target to enhance cancer control.

| S-EPMC9809269 | biostudies-literature

Transcriptional regulation by IRF1 and IRF2 in the mouse DC3.2 cell line in the presence or absence of interferon

Project description:We analyzed the classes of genes influenced by IRF1 and IRF2 under basal conditions and upon stimulation with interferon.

2019-06-21 | GSE133089 | GEO

IRF2 maintains the stemness of colonic stem cells by limiting physiological stress from interferon

Project description:The physiological stresses that diminish tissue stem-cell characteristics remain largely unknown. We previously reported that type I interferon (IFN), which is essential for host antiviral responses, is a physiological stressor for hematopoietic stem cells (HSCs) and that interferon regulatory factor-2 (IRF2), which attenuates IFN signaling, maintains the stemness of HSCs. Here, we explore the role of IRF2 in maintaining colonic epithelial stem cells (CoSCs). In mice with a conditional Irf2 deletion in the intestinal epithelium (hereafter Irf2ΔIEC mice), both the number and the organoid-forming potential of CoSCs was markedly reduced. Consistent with this finding, the ability of Irf2ΔIEC mice to regenerate colon epithelium after injury by dextran sodium sulfate (DSS) was severely impaired, independently of microbial dysbiosis. Mechanistically, CoSCs differentiated prematurely into transit-amplifying (TA) cells in Irf2ΔIEC mice, which might explain their low CoSC counts. A similar phenotype was induced in wild-type mice by repeated injections of low doses of poly(I:C), which induces type I IFN. Collectively, we demonstrated that chronic IFN signaling physiologically stresses CoSCs. This study provides new insight into the molecular mechanisms that maintain functional CoSCs throughout life.

2020-09-18 | GSE107142 | GEO

Precision targeting of beta-catenin induces tumor reprogramming and immunity in hepatocellular cancers [Bulk RNA-seq CTNNB1/MET/IRF2]

Project description:First-line immune checkpoint inhibitor (ICI) combinations have shown responses in subsets of patients with advanced hepatocellular carcinoma (HCC). Nearly half of patients are Wnt active with mutations in CTNNB1 (encoding for beta-catenin), AXIN1/2, or APC, and demonstrate limited benefit to ICI due to an immunosuppressive tumor microenvironment. We investigated a novel siRNA encapsulated in lipid nanoparticle targeting CTNNB1 (LNP-CTNNB1) in multiple beta-catenin-mutated immunocompetent HCC mouse models, observing complete response. Integrated single-cell and spatial transcriptomics revealed complete cellular and zonal reprogramming of CTNNB1-mutated tumors, and a spatiotemporal shift in innate immune surveillance with intra-tumoral pro-inflammatory myeloid infiltration following LNP-CTNNB1 intervention. beta-catenin knockdown initiated tumor cell-intrinsic type I/II interferon signaling accompanied by IRF2 upregulation, which was suppressed in CTNNB1-mutated HCCs. IRF2 re-expression in beta-catenin-mutated HCC restored adaptive tumor immunity with increased CD4+ T cells and impaired recruitment of resident T regulatory cells. Finally, LNP-CTNNB1 synergized with ICI in advanced-stage disease through increasing intra-tumoral recruitment of cytotoxic T cells. In summary, RNAi-mediated inhibition of CTNNB1 is efficacious as monotherapy and in combination with ICI in CTNNB1-mutated HCCs through remodeling both tumor cell intrinsic signaling and global immune surveillance, thus providing rationale for clinical investigations.

2025-05-02 | GSE270415 | GEO

Interferon inducible GBPs restrict Burkholderia thailandensis motility induced cell-cell fusion

Project description:Innate immunity responds to pathogens by producing alarm signals and activating pathways that make host cells inhospitable for pathogen replication. The intracellular bacterium Burkholderia thailandensis invades the cytosol, hijacks host actin, and induces cell fusion to spread to adjacent cells, forming multinucleated giant cells (MNGCs) which promotes bacterial replication. We show that type I interferon (IFN) restricts macrophage MNGC formation during B. thailandensis infection. Guanylate-binding proteins (GBPs) expressed downstream of type I IFN were required to restrict MNGC formation through inhibition of Arp2/3-dependent actin motility during infection. GTPase activity and the CAAX prenylation domain were required for GBP2 recruitment to B. thailandensis, which restricted bacterial actin polymerization required for MNGC formation. Consistent with in vitro macrophages, Gbp2-/- Gbp5-/-, GbpChr3-KO mice were more susceptible to intranasal infection with B. thailandensis than wildtype mice. Our findings reveal that IFN and GBPs play a critical role in restricting cell-cell fusion during infection

2021-08-23 | GSE143936 | GEO

Interferon inducible GBPs restrict Burkholderia thailandensis motility induced cell-cell fusion

Project description:Interferon inducible GBPs restrict Burkholderia thailandensis motility induced cell-cell fusion

| PRJNA602234 | ENA

HCFC2 needed for IRF1- and IRF2-dependent Tlr3 transcription, and for survival during viral infections

Project description:IRF1 and IRF2 are transcription factors for interferon stimulated genes. HCFC2 facillitates their assoication with DNA targets and maintains the proper transcitpion of target genes.

2017-12-23 | GSE100436 | GEO

IRF2 regulates macrophages apoptosis through a STAT1/3 and Caspase-1-dependent mechanism

Project description:Using microarray gene expression profiling of liver RNA samples rerived from IRF2+/+ and IRF2-/- mice treated with saline or LPS, we identified >40 genes that were significantly down-regulated in IRF2 -/- mice, including STAT3 which has been reported to regulate apoptosis. Keywords: compound treatment design We compared gene expression in IRF2+/+ and IRF2-/- mice treated with Saline or LPS for 3 or 6 hours. Two repeats were done for the LPS treatments. The total number of arrays is 6.

2007-09-01 | E-GEOD-5907 | biostudies-arrayexpress

Differences in gene expression between WT and IRF2 KO cells

Project description:Gasdermin-D (GSDMD) is cleaved by caspase-1/4/11 in response to canonical and non-canonical inflammasome activation. Upon cleavage, GSDMD oligomerizes and forms membrane pores, resulting in IL-1Î² secretion, pyroptotic cell death and inflammatory pathologies including periodic fever syndromes and septic shock â a plague on modern medicine. The transcriptional machinery that drives the expression of GSDMD is unknown. Here we show that IRF2, a member of the interferon-regulatory factor (IRF) family, is essential for the transcriptional activation of GSDMD. A forward genetic screen with ethyl-N-nitrosourea (ENU)-mutagenized mice unequivocally linked IRF2 to inflammasome signaling. Indeed, GSDMD transcript levels were highly attenuated in Irf2â/â macrophages upon Irf2 deficiency in macrophages, endothelial cells, and multiple organs, corresponding to attenuated IL-1Î² secretion and inhibited pyroptosis. Mechanistically, IRF2 binds a previously uncharacterized site within the GSDMD promoter to directly drive GSDMD transcription for execution of pyroptosis in response to canonical and non-canonical inflammasome activation. Our data illuminate a prominent transcriptional mechanism for the expression of GSDMD, a key mediator of inflammatory pathologies.

2019-05-21 | GSE130195 | GEO

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