Transcriptional control of NK cell metabolism

项目摘要 自然杀伤(NK)细胞是宿主先天免疫系统的重要组成部分，它检测和 消除受病毒感染的细胞。缺乏NK细胞的新生儿和免疫受损患者 极易受病毒感染的。特别是，人类巨细胞病毒(HCMV)可导致严重的 对这些人来说，健康并发症或危及生命。小鼠巨细胞病毒是一种 用于研究NK细胞对人巨细胞病毒的反应的准确和稳健的模型。使用MCMV感染 小鼠，我们发现NK细胞具有新的获得性免疫功能，如克隆性 扩展和长寿的记忆。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 自然杀伤细胞的一般生物学，以及这些强大的天然淋巴细胞能够 对病原体入侵的中介保护。为此，我们最近确定了几个 可能影响NK细胞对MCMV感染的反应的转录和代谢途径。 基于这一令人兴奋的初步数据，我们目前的R01拨款建议使用尖端代谢组学 和新设计的转基因小鼠模型来研究抗病毒NK细胞的新陈代谢 转录调控的。在目标1中，我们试图了解促炎细胞因子和状态 转录因子家族在巨细胞病毒感染过程中对NK细胞代谢的调控。在目标2中，我们将 测定抗病毒NK细胞有氧糖酵解和脂肪酸氧化的需要量 条件消融分别编码LDHA和CPT1a的基因。在目标3中，我们将确定 转录因子Bhlhe40是否调节效应器NK的线粒体代谢和适应性 对抗巨细胞病毒感染的细胞。综上所述，R01建议中的研究将大大增加我们的 了解NK细胞参与转录和代谢的潜在机制 在病毒感染期间进行防御，并建立利用NK细胞的新的翻译范例 用于免疫和针对传染病的治疗策略的细胞隔间。

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.