Transcriptional control of NK cell metabolism

项目摘要 自然杀伤（NK）细胞构成宿主先天性免疫系统的重要分支，其检测并 消除病毒感染的细胞。缺乏NK细胞的新生儿和免疫受损患者， 极易受到病毒感染特别地，人巨细胞病毒（HCMV）可引起严重的 健康并发症或危及这些人的生命。小鼠巨细胞病毒（MCMV）是一种 用于研究NK细胞对HCMV的应答的准确且稳健的模型。使用MCMV感染 在小鼠中，我们发现NK细胞具有新的适应性免疫特征，如克隆性免疫， 扩展和长寿记忆。在过去的十年里，我们的实验室已经发现了许多细胞 以及NK细胞记忆的分子机制。我们的长期目标是了解 NK细胞的一般生物学，以及这些强大的先天淋巴细胞可以 介导对病原体入侵的保护。为此，我们最近确定了几个 转录和代谢途径，可能会影响NK细胞对MCMV感染的反应。 基于这一令人兴奋的初步数据，我们目前的R01基金建议使用尖端代谢组学 和新设计的转基因小鼠模型，以研究抗病毒NK细胞的代谢如何在 转录调控。在目标1中，我们试图了解促炎细胞因子和STAT是如何在细胞内表达的。 MCMV感染期间NK细胞代谢的转录因子家族控制。在目标2中，我们将 确定抗病毒NK细胞中有氧糖酵解和脂肪酸氧化的需要， 分别对编码LDHA和CPT 1a的基因进行条件性切除。在目标3中，我们将确定 转录因子Bhlhe40是否调节效应NK细胞的线粒体代谢和适应性 抵抗MCMV感染的细胞。总而言之，R01提案中的研究将大大提高我们的 了解NK细胞在转录和代谢中的作用机制， 在病毒感染过程中宿主防御，并建立新的翻译模式，利用NK细胞 细胞隔室用于免疫和针对传染病的治疗策略。

Project Summary Natural killer (NK) cells comprise an important arm of the host innate immune system that detects and eliminates virus-infected cells. Newborns and immune-compromised patients lacking NK cells are extremely susceptible to viral infection. In particular, human cytomegalovirus (HCMV) can cause severe health complications or be life-threatening in these individuals. Mouse cytomegalovirus (MCMV) is an accurate and robust model for investigating NK cell responses against HCMV. Using MCMV infection in mice, we have discovered that NK cells possess novel adaptive immune features such as clonal expansion and long-lived memory. In the past decade, our laboratory has uncovered many of the cellular and molecular mechanisms underlying NK cell memory. Our long-term goals are to understand the general biology of NK cells, and the molecular basis by which these powerful innate lymphocytes can mediate protection against pathogen invasion. To this end, we have recently identified several transcriptional and metabolic pathways that may influence the NK cell response against MCMV infection. Based on this exciting preliminary data, our current R01 grant proposes to use cutting edge metabolomics and newly engineered transgenic mouse models to study how metabolism in antiviral NK cells in transcriptionally regulated. In Aim 1, we seek to understand how proinflammatory cytokines and the STAT family of transcription factors control of NK cell metabolism during MCMV infection. In Aim 2, we will determine the requirement for aerobic glycolysis and fatty acid oxidation in antiviral NK cells using conditional ablation of genes encoding LDHA and CPT1a, respectively. In Aim 3, we will determine whether the transcription factor Bhlhe40 regulates mitochondrial metabolism and fitness in effector NK cells fighting MCMV infection. Altogether, the studies in this R01 proposal will greatly increase our understanding of the underlying transcriptional and metabolic mechanisms whereby NK cells contribute to host defense during viral infection, and establish novel translational paradigms for harnessing the NK cell compartment for immunization and therapeutic strategies against infectious diseases.