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STING-dependent activation of Natural Killer cells by viral and tumor DNA

病毒和肿瘤 DNA 对自然杀伤细胞的 STING 依赖性激活

基本信息

批准号：
10352399
负责人：
DAVID H RAULET
金额：
$ 45.3万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10352399
关键词：
Address Alleles Antigen-Presenting Cells Antitumor Response Antiviral Response Binding Bone Marrow CRISPR interference Cancer Model Cells Chimera organism Cre driver Critical Pathways DNA DNA Viruses DNA biosynthesis Data Defect Dendritic Cells Dinucleoside Phosphates Enzymes Event Failure Genetic Engineering Genetic Transcription Genetically Engineered Mouse Graft Rejection Herpesviridae Immune Immune response Immune signaling In Vitro Infection Injections Interferon Type I Interferons Investigation Knockout Mice Malignant Neoplasms Mammalian Cell Mediating Mediator of activation protein Membrane Transport Proteins Modeling Mus NK Cell Activation Natural Killer Cells Neoplasm Transplantation Pathway interactions Periodicity Play Process Production Proteins Research Role SLC19A1 gene Series Shapes Signal Pathway Signal Transduction Site Stimulator of Interferon Genes Sting Injury T cell response T-Lymphocyte Testing Viral Viral Cancer Virus Virus Diseases anti-tumor immune response base cancer cell cancer immunotherapy cell transformation conditional knockout cytokine genetic approach genome-wide immune activation in vivo inhibitor intercellular communication macrophage neoplastic cell neutrophil novel novel strategies pathogen prevent receptor response small molecule treatment response tumor tumor DNA tumor microenvironment viral DNA

项目摘要

The cGAS-STING pathway senses cytosolic DNA in infected cells and cancer cells and triggers production of type I interferon and other cytokines, thus eliciting immune responses. Deficiency in the pathway prevents T cell responses to several viruses and to transplanted tumor lines. Our new results show that the pathway is critical for activating spontaneous NK cell responses against cancer, and virus infections. Furthermore, in probing the underlying mechanisms, our research has uncovered a new cellular mechanism whereby cGAS and STING activate immune responses. Using genetic approaches, we found that the NK response to transferred tumor cells depends on cGAS expression in tumor cells and STING expression in host cells. We interpret these data to indicate that cGAS activation is the key event that occurs in infected or transformed cells resulting in the production of the cyclic dinucleotide cGAMP. cGAMP is then transferred from the infected/transformed cells to other immune cells, such as antigen presenting cells, which are induced to initiate the immune response. Hence, we propose that cGAMP transfer between cells is a fundamental mechanism in immune activation. In considering how cGAMP is transferred between cells, we hypothesized that specific membrane transporters must play a role. Using a genome-wide CRISPRi screen, we identified a transporter molecule that specifically imports cGAMP into cells. Using a series of knockout mice and conditional knockout mice, and cellular manipulations and transfers, we propose to test the requirement of cGAS-STING signaling in NK and T cell responses to cancer and DNA viruses, the generality of the requirement of the transfer mechanism in viral infections and cancer models and for T cell and NK cell responses, the roles of the newly identified transporters in the process, and to define the specific cells that must import the cGAMP for immune responses to occur. Specifically, we will: (1) Determine the sites of action of cGAMP and STING and intercellular transfer of cGAMP in anti-viral responses, including NK and T cell responses; (2) Determine sites of action of cGAMP and STING and intercellular transfer of cGAMP in T cell responses to cancer, in transfer models and GEM cancer models; (3) Determine roles of cGAMP transporters in anti-viral and anti-tumor and immune responses. Using conditional knockout mice and inhibitor studies, we will test their function in anti-herpesvirus and anti-tumor responses, including a GEM model of cancer.

cGAS-STING途径在感染细胞和癌细胞中感知胞质DNA并触发产生