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（由申请人提供）：该提案的一个核心科学问题是在研究典型先天环境（巨噬细胞）中的 STING 时，寻找有关 STING（一种典型的胞质 DNA 先天免疫传感器）在 T 细胞激活程序中的作用的额外证据。，我们通过搜索公共数据库确定了淋巴组织中高水平的 STING mRNA，我们对此进行了进一步的实验，其中我们使用合成的 STING 激动剂 DMXAA 来观察 T 细胞的直接激活，从而产生我们接下来开展的研究使我们发现了具有范式转变潜力的发现，首先，我们检测到 DMXAA 激活的 T 细胞产生 I 型干扰素。其伴随着数百个 ISG 的激活。有证据表明转录激活因子 IRF3 和 TBK1 激酶在 STING 下游被激活。其次，我们确定了配体依赖性缺失的影响。 T 细胞中的 STING。由于 STING 功能丧失等位基因的广泛存在（20%）与人类的多种病理有关，因此必须考虑突变等位基因对 T 细胞的可能影响。响应 STING 激活而产生 I 型 IFN、TNF 和其他炎症细胞因子可能对许多疗法（包括癌症治疗）产生重要影响：DMXAA 最初因其抗肿瘤和抗血管化作用而被作为癌症药物进行测试；还报道了刺激先天性和适应性免疫反应，但我们的数据表明，STING 的基因消除严重削弱了 TCR 连接后 T 细胞的增殖能力，暗示用 DMXAA 激活 STING 也会抑制 TCR 诱导的免疫反应。这两个观察结果使我们得出了一种新模型，该模型可能通过与下游组件之一相互作用来促进 TCR 信号传导，但在识别 DMXAA 后从 TCR 中转移，因此 DMXAA 成为一种工具。尽管这还需要进一步支持，但这一假设的价值非常新颖，因为它将改变我们感知 T 细胞的方式，这可能会为这一假设提供支持。实验环境下，可以通过使用体外慢病毒或艾滋病毒感染来获得进一步的证据。