NK cell responses to JC polyomavirus

大多数健康人持续感染人类多瘤病毒JC(JCPyV)，但没有明显的 后果，然而在免疫受损的宿主中，JCPyV可以导致一种通常是致命的疾病--进行性 多灶性白质脑病(PML)。目前没有有效的治疗方法来预防或治疗PML和 迫切需要新的基于免疫的治疗方法来降低与以下疾病相关的发病率和死亡率 PML。传统上，自然杀伤(NK)细胞被视为天然免疫系统的非特异性效应细胞。 它们在防御病毒感染方面发挥着关键作用。没想到的是，最近有证据表明，除了 它们能够快速清除感染病毒的细胞，而不需要事先进行抗原致敏，NK细胞也 表现出适应性免疫功能。已经在人类之间发现了不同形式的适应能力 NK细胞亚群，包括真实抗原特异性记忆NK细胞和适应性NK细胞的报道 具有增强的抗体依赖功能。适应性NK细胞亚群具有强大的抗病毒作用 病毒特异性记忆NK细胞的特性和保护已在小鼠模型中得到证实。 重要的是，越来越多的证据表明，NK细胞可以介导对JCPyV的抗病毒反应。特别是， 我们的初步数据显示，NK细胞对JCPyV多肽有很强的反应能力，分离和克隆了单个 JCPyV特异性NK细胞，并降低PML患者JCPyV特异性抗体依赖的细胞毒作用。 基于这些数据，我们假设NK细胞和激发NK细胞反应的抗体在 JCPyV的致病机制。具体地说，我们建议以我们的初步数据为基础来调查 假设特定的NK细胞亚群可以介导针对JCPyV和JCPyV的有效抗病毒反应 通过两个有针对性的独立目标保护免疫功能低下的患者免受PML的侵袭：(I)定义 NK细胞控制JCPyV的关键机制；以及(Ii)评估JCPyV特异性的作用 调节NK细胞抗JCPyV活性的抗体。如果成功，这些创新研究的结果 将为人类对JCPyV的免疫反应提供新的知识，并为开发 利用NK细胞功能对抗JCPyV的新免疫治疗方法。

Most healthy individuals are persistently infected with the human polyomavirus JC (JCPyV) without significant consequences, yet in immunocompromised hosts, JCPyV can cause an often fatal disease -- progressive multifocal leukoencephalopathy (PML). There is currently no effective treatment to prevent or treat PML and novel immune-based therapies are urgently needed to decrease the morbidity and mortality associated with PML. Classically, natural killer (NK) cells are viewed as nonspecific effector cells of the innate immune system that play critical roles in defense against viral infections. Unexpectedly, it was recently demonstrated that besides their ability to rapidly eliminate virus-infected cells without the need for prior antigen sensitization, NK cells also exhibit adaptive immune functions. Different forms of adaptive capabilities have been identified among human NK cell subpopulations, including reports of true antigen-specific memory NK cells as well as adaptive NK cells with enhanced antibody-dependent functions. Adaptive NK cell subsets are endowed with potent anti-viral properties and protection mediated by virus-specific memory NK cells has been demonstrated in mouse models. Importantly, increasing evidence suggest that NK cell can mediate anti-viral responses to JCPyV. In particular, our preliminary data now show potent responses to JCPyV peptides by NK cells, isolation and cloning of single JCPyV-specific NK cells, and reduced JCPyV-specific antibody-dependent cellular cytotoxicity in PML patients. Based on these data, we hypothesize that NK cells and antibodies eliciting NK cell responses play a role in JCPyV pathogenesis. Specifically, we propose to build on our preliminary data to investigate the overarching hypothesis that specific subsets of NK cells can mediate potent anti-viral responses against JCPyV and protect immunocompromised patients against PML, through two focused independent Aims: (i) Define mechanisms crucial to control of JCPyV by NK cells; and (ii) Evaluate the role played by JCPyV-specific antibodies in modulating NK cell activity against JCPyV. If successful, the results of these innovative studies will contribute new knowledge of human immune response against JCPyV and provide the rationale to develop novel immunotherapeutic approaches to harness NK cell function against JCPyV.