Lymphopenia-induced T cell exhaustion in STING gain-of-function mouse model
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ABSTRACT:
PROVIDER: PRJEB71462 | ENA |
REPOSITORIES: ENA
Dataset's files
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| ERR12383106_1.fastq.gz | Fastqsanger.gz | |||
| ERR12383106_2.fastq.gz | Fastqsanger.gz | |||
| ERR12383107_1.fastq.gz | Fastqsanger.gz | |||
| ERR12383107_2.fastq.gz | Fastqsanger.gz | |||
| ERR12383108_1.fastq.gz | Fastqsanger.gz |
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Project description:STING gain-of-function (GOF) mutations lead to T cell lymphopenia, in the context of severe combined immunodeficiency (SCID) for STING GOF V154M mice. This T cell lymphopenia, which is of central origin, has been described as type I IFN independent and associated with dysfunctions of the rare mature T cells found in the periphery. To better describe the biological mechanisms of these dysfunctions, we performed a transcriptomic analysis by RNA-seq on sorted splenic CD4+ and CD8+ mature T cells from STING GOF mice. We highlighted an unexpected T cell exhaustion phenotype that could partly explain their dysfunctions. Acquired very early in life, but only once the peripheral environment is reached, the phenotype appeared to depend neither on type I IFNs, nor on the intrinsic activation of STING in T or stromal cells. Mechanistically, the few mature T cells reaching the periphery seem to be rapidly impacted by the lymphopenic environment through increased antigenic and IL-7 stimulations that could lead to their exhaustion. By using STING GOF long term-hematopoietic stem cells (LT-HSC) transplantations with supportive wild-type bone marrow (BM) cells, we prevented the T cell exhaustion of STING GOF T cells in the resulting non lymphopenic context. With the support of lymphopenic RAG1 hypomorphic mice developing the phenotype, our data uncover a lymphopenia-mediated T cell exhaustion mechanism in STING GOF mice, for which a synergistic effect of the mutation is also envisaged.
2024-01-07 | E-MTAB-13658 | biostudies-arrayexpress
Project description:Patients afflicted with STING gain-of-function mutations frequently present with debilitating interstitial lung disease (ILD) that is recapitulated in mice expressing the STINGV154M mutation (VM). Prior radiation chimera studies revealed an unexpected and critical role for non-hematopoietic cells in initiating ILD. To identify STING-expressing non-hematopoietic cell types required for the development of ILD, we generated a conditional knock-in (CKI) model and directed expression of the VM allele to hematopoietic cells, fibroblasts, epithelial cells, or endothelial cells. Only endothelial cell-targeted VM expression resulted in enhanced recruitment of immune cells to the lung associated with chemokine expression and the formation of bronchus-associated lymphoid tissue, as seen in the parental VM strain. These findings reveal the importance of endothelial cells as instigators of STING-driven lung disease and suggest that therapeutic targeting of STING inhibitors to endothelial cells could potentially mitigate inflammation in the lungs of SAVI patients or patients afflicted with other ILD-related disorders.
2024-05-29 | GSE260893 | GEO
Project description:Endothelial Cell Expression of a STING Gain-of-function Mutation Initiates Pulmonary Lymphocytic Infiltration
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Project description:Constitutive activation of STING by gain-of-function mutations triggers manifestation of the systemic autoinflammatory disease STING-associated vasculopathy with onset in infancy (SAVI) in humans and in mice. Murine SAVI is characterized by T cell lymphopenia, severe inflammatory interstitial lung disease, neuroinflammation and neurodegeneration with only limited contribution of type I interferon signaling. Here, we show that pharmacologic inhibition of TNF signaling in SAVI mice improved T cell lymphopenia, but had no effect on interstitial lung disease. However, complete blocking of TNF receptor signaling by knocking out TNFR1 and TNFR2 in SAVI mice rescued both, loss of thymocytes as well as interstitial lung disease. Furthermore, chronic STING signaling in lung endothelial cells of diseased mice enhanced transcription of cytokines, chemokines and adhesions proteins resulting in increased transendothelial migration of neutrophils across the endothelial barrier that could be reverted by genetic inactivation of TNFR1 and 2. Thus, our results demonstrate a pivotal role of TNFR-signaling in the development of SAVI-associated lung disease and suggest this pathway as promising target to ameliorate human SAVI
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Project description:Pro-Inflammation Associated with a Gain-of-Function Mutation (R284S) in the Innate Immune Sensor STING
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Project description:Radioresistant Cells in STING Gain-of-function Mice Initiate Lymphocyte-dependent Lung Inflammation and IFNγ-dependent Mortality
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Project description:STING transmits signals downstream of the cytosolic DNA sensor cGAS, leading to transcriptional up-regulation of cytokines. However, components of the STING signaling pathway, such as IRF3 and IFNAR1, are not essential for autoinflammatory disease in STING gain-of-function (SAVI) mice. Recent findings indicate that STING can also function as a proton channel that deacidifies the Golgi. Since pH impacts Golgi enzyme activity, protein maturation, and trafficking, we hypothesized that STING proton channel activity influences multiple Golgi functions. Here, we show that STING-mediated proton efflux non-transcriptionally regulates Golgi trafficking of protein cargos. This process requires the Golgi-associated protein ArfGAP2, a cell type-specific dual regulator of STING-mediated proton efflux and signaling. Deletion of ArfGAP2 in hematopoietic and endothelial cells markedly reduces STING-mediated cytokine and chemokine secretion, immune cell activation, and autoinflammatory pathology in SAVI mice. Thus, ArfGAP2 facilitates STING-mediated signaling and cytokine release in hematopoietic cells, significantly contributing to autoinflammatory disease pathogenesis.
2024-11-30 | PXD058416 | Pride
Project description:Activation of the STING (Stimulator of Interferon Genes) pathway by microbial or self-DNA, as well as cyclic di nucleotides (CDN), results in the induction of numerous genes that suppress pathogen replication and facilitate adaptive immunity. However, sustained gene transcription is rigidly prevented to avoid lethal STING-dependent pro-inflammatory disease by mechanisms that remain unknown. We demonstrate here that after autophagy-dependent STING delivery of TBK1 (TANK-binding kinase 1) to endosomal/lysosomal compartments and activation of transcription factors IRF3 (interferon regulatory factors 3) and NF-κB (nuclear factor kappa beta), that STING is subsequently phosphorylated by serine/threonine UNC-51-like kinase (ULK1/ATG1) and IRF3 function is suppressed. ULK1 activation occurred following disassociation from its repressor adenine monophosphate activated protein kinase (AMPK), and was elicited by CDN’S generated by the cGAMP synthase, cGAS. Thus, while CDN’s may initially facilitate STING function, they subsequently trigger negative-feedback control of STING activity, thus preventing the persistent transcription of innate immune genes. Total RNA obtained from primary STING deficient mouse embryonic fibroblast reconstituted with mSTING (W), S365A variant (A), or S365D variant (D). These cells were transfected with dsDNA (ISD) for 3 hours.
2013-10-10 | E-GEOD-51199 | biostudies-arrayexpress
Project description:Pediatric patients with constitutively active mutations in the cytosolic dsDNA sensing adaptor STING develop an autoinflammatory syndrome known as STING Associated Vasculopathy with onset in Infancy (SAVI). SAVI patients have elevated interferon stimulated gene expression and suffer from interstitial lung disease (ILD) with lymphocyte predominate bronchus associated lymphoid tissue (BALT). Mice harboring SAVI mutations (STING V154M or VM) that recapitulate human disease also develop lymphocyte rich BALT formation. Ablation of either T or B lymphocytes prolongs survival of SAVI mice, but lung immune aggregates persist, indicating that T cells and B cells can independently be recruited as BALT. VM T cells produced IFNγ and IFNγR deficiency prolonged the survival of SAVI mice; however, T cell dependent recruitment of infiltrating myeloid cells to the lung was independent of IFNγ. Lethally irradiated VM recipients fully reconstituted with WT BM-derived cells still developed ILD, pointing to a critical role for VM-expressing radioresistant parenchymal and/or stromal cells in the recruitment and activation of pathogenic lymphocytes. We identified lung endothelial cells as radioresistant cells which express STING. Transcriptional analysis of VM endothelial cells revealed upregulation of chemokines, pro-inflammatory cytokines, and genes associated with antigen presentation. Together, our data show that VM-expressing radioresistant cells play a key role in the initiation of lung disease in VM mice and provide new insights for the treatment of SAVI patients, with implications for ILD associated with other connective tissue disorders.
2022-02-11 | GSE196342 | GEO
Project description:Chronic stimulation of innate immune pathways by microbial agents or damaged tissue is known to promote inflammation-driven tumorigenesis by unclarified mechanisms1-3. Here we demonstrate that mutagenic 7,12-dimethylbenz(a)anthracene (DMBA), etoposide or cisplatin induces nuclear DNA leakage into the cytosol to intrinsically activate STING (Stimulator of Interferon Genes) dependent cytokine production. Inflammatory cytokine levels were subsequently augmented in a STING-dependent extrinsic manner by infiltrating phagocytes purging dying cells. Consequently, STING-/- mice, or wild type mice adoptively transferred with STING-/- bone marrow, were almost completely resistant to DMBA-induced skin carcinogenesis compared to their wild type counterparts. Our data emphasizes, for the first time, a role for STING in the induction of cancer, sheds significant insight into the causes of inflammation-driven carcinogenesis, and may provide therapeutic strategies to help prevent malignant disease Total RNA obtained from wild type murine embryonic fibroblasts (WT MEFs), STING deficient MEFs (SKO), Trex1 deficient MEFs (TKO), and both STING and Trex1 deficient MEFs (STKO) treated with DMBA and examined cytokine production by these cells.
2014-05-31 | E-GEOD-57603 | biostudies-arrayexpress