Activation of STING-mediated pathway(s) in T cells

T 细胞中 STING 介导的通路的激活

基本信息

批准号：
9229505
负责人：
Alexander Poltorak
金额：
$ 24.75万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-19 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9229505
关键词：
Ablation Adaptor Signaling Protein Address Agonist Alleles Antigens Antineoplastic Agents Asians Attenuated Autoimmunity Bacteria Binding Biochemical Blood Vessels Cell physiology Cells Cytotoxic T-Lymphocytes DNA Data Databases Defense Mechanisms Dimethylxanthenone Acetic Acid Environment Frequencies Future General Population Genes Genetic Genetic Polymorphism HIV Infections Human IRF3 gene Immune Immune response In Vitro Inflammatory Innate Immune Response Interferon Type I Interferons Lead Ligands Ligation Link Lymphoid Tissue Mediating Messenger RNA Modeling Mus Myeloid Cells Nucleic Acids Nucleotides Pathogenicity Pathologic Processes Pathology Pathway interactions Periodicity Peripheral Phosphotransferases Physiological Play Population Production Proliferating Proteins Reporting Role Signal Pathway Signal Transduction Solid Source Stimulus Surface T cell response T-Cell Activation T-Cell Proliferation T-Lymphocyte TBK1 gene TCR Activation TNF gene Testing Therapeutic Transcription Coactivator Up-Regulation Vaccination Vascularization Virus adaptive immune response cancer therapy cell type clinically relevant cytokine design ds-DNA experimental study genetic signature in vivo insight loss of function macrophage mutant novel pathogen prevent programs public health relevance receptor response sensor tool tumor

项目摘要

DESCRIPTION (provided by applicant): A central scientific question of this proposal's is finding additional evidence for the role of STING, a typical innate immune sensor of cytosolic DNA, in activation program in T cells. While studying STING in typical innate environment (macrophages), we identified via search of public database high levels of STING mRNA in lymphoid tissues, which prompted us to set up further experiments, in which we used the synthetic STING- agonist DMXAA to observe direct activation of T cells resulting in production of type I IFN followed by significant upregulation of multiple interferon stimulated genes (ISG). We next set up studies that led us to discoveries with paradigm-shifting potential. First, we detected production of type I interferon by DMXAA-activated T cells which is accompanied by activation of hundreds of ISGs. This activation program is supported by evidence showing that transcriptional activator IRF3 and TBK1 kinase is activated downstream of STING. Second, we identify ligand-independent effects of the loss of STING in T cells. Because of widespread (20%) of loss-of-function allele of STING is linked to several pathologies in humans, possible effect of the mutant allele on T cells has to be considered. Our subsequent discovery that T cells can produce type I IFNs, TNF, and other inflammatory cytokines in response to STING activation may have important implications for many therapies, including cancer treatments: DMXAA was initially tested as a cancer drug because of its anti-tumor and anti-vascularization effects; DMXAA was also reported to stimulate both innate and adaptive immune responses but the mechanism was unknown. Our data show that genetic ablation of STING severely attenuates the ability of T cells to proliferate upon TCR-ligation. Interestingly, activation of STING with DMXAA also inhibits TCR-induced proliferation. These two observations lead us to a new model that has STING promote TCR signaling, possibly via interaction with one of the downstream components, but undergoing translocation away from TCR following recognition of DMXAA. Thus DMXAA becomes a tool for tweaking TCR-activation in T cells. Although this has to be further supported, the value of this hypothesis is highly novel because it will change the way we perceive T cells. We have designed experiments, which may provide support for this hypothesis. In experimental settings, further evidence could be obtained by using in vitro lentiviral or HIV infection.

描述（由适用提供）：该提案的一个核心科学问题是为T细胞中的激活程序中的典型先天性免疫传感器找到sting的作用的其他证据。 While studying STING in typical innate environment (macrophages), we identified via search of public database high levels of STING mRNA in lymphoid tissues, which prompted us to set up further experiments, in which we used the Synthetic STING-agonist DMXAA to observe direct activation of T cells resulting in production of type I IFN followed by significant upregulation of multiple interferon stimulated genes (ISG).接下来，我们进行了研究，这使我们发现了范式转移潜力的发现。首先，我们通过DMXAA激活的T细胞检测到I型干扰素的产生，这是通过激活数百个ISG来完成的。该激活程序得到了证据，表明转录激活剂IRF3和TBK1激酶是在刺激的下游激活的。其次，我们确定了T细胞中刺激损失的配体无关的作用。由于刺激性等位基因的宽度（20％）与人类的几种病理有关，因此必须考虑突变等位基因对T细胞的可能影响。我们随后发现，T细胞可以产生I型IFN，TNF和其他炎症细胞因子，以响应刺痛激活，可能对许多疗法具有重要意义，包括癌症治疗：DMXAA最初是由于其抗肿瘤和抗血管化作用而被视为癌症药物的；据报道，DMXAA既刺激先天和适应性免疫回报，却是未知的。我们的数据表明，刺痛的遗传消融严重削弱了T细胞在TCR结合后增殖的能力。有趣的是，用DMXAA激活刺激也抑制了TCR诱导的增殖。这两个观察结果使我们建立了一个新模型，它具有刺激性的TCR信号传导，这是通过与下游组件之一的相互作用来促进TCR信号传导的，但是在识别DMXAA之后，将转换远离TCR。 DMXAA成为调整TCR激活T细胞中TCR激活的工具。尽管必须进一步支持这一点，但该假设的价值是高度新颖的，因为它将改变我们感知T细胞的方式。我们设计了实验，可以为这一假设提供支持。在实验环境中，可以通过使用体外慢病毒或HIV感染获得进一步的证据。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Wild-derived mice: from genetic diversity to variation in immune responses.

野生小鼠：从遗传多样性到免疫反应的变化。

DOI：
10.1007/s00335-018-9766-3
发表时间：
2018
期刊：
Mammalian genome : official journal of the International Mammalian Genome Society
影响因子：
0
作者：
Poltorak,Alexander;Apalko,Svetlana;Sherbak,Sergei
通讯作者：
Sherbak,Sergei