Metabolic Regulation of Natural Killer Cell Activation

自然杀伤细胞激活的代谢调节

• 批准号: 10789052
• 负责人: MEGAN Anne COOPER
• 金额: $ 30万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-05 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10789052
• 关键词: Activated Natural Killer Cell; Acute; Adoptive Transfer; Affect; Agonist; Antibodies; Cell Differentiation process; Cell Maturation; Cell physiology; Cells; Citrates; Clinical Trials; Data; Defect; Dependence; Disease; Effector Cell; Environment; FRAP1 gene; Genetic Models; Genetic Transcription; Glucose; Glycolysis; Goals; Health; Herpesviridae Infections; Homeostasis; Human; Immune; Immunity; Immunologic Surveillance; Immunotherapy; In Vitro; Infection; Inflammatory; Interferon Type II; Interleukin-15; Knowledge; Ligands; Lymphocyte; Malates; Mediating; Metabolic; Metabolic Pathway; Metabolic stress; Metabolism; Modeling; NK Cell Activation; NK cell therapy; Natural Killer Cells; Oxidative Phosphorylation; Pathway interactions; Patients; Play; Process; Production; Recurrence; Regulation; Research; Role; Testing; Transcript; Transcriptional Regulation; Up-Regulation; Viral; Virus; Virus Diseases; c-myc Genes; cancer cell; cell killing; cytokine; flexibility; glucose metabolism; human disease; improved; in vivo; in vivo evaluation; inhibitor; interest; mTOR inhibition; metabolomics; neoplastic cell; receptor; response; transcription factor; tumor; virus related cancer

Project Summary The long-term goal of this project is to determine the metabolic regulation of NK cell effector functions to improve our understanding of basic mechanisms of NK cell activation in health and disease. Natural killer (NK) cells are innate immune lymphocytes that serve as a critical first line defense against infection, particularly viruses, and are important for tumor immunosurveillance. NK cells mediate their effects via two mechanisms: production of cytokines (especially IFN-gamma) and target cell killing. NK cell effector functions can be triggered by inflammatory cytokines or engagement of germline-encoded activating receptors whose ligands are displayed by infected and/or tumor cells. Metabolic regulation plays a key role in many aspects of immunity, including in NK cell response to viral infection. We previously demonstrated that stimulation of naïve, fresh NK cells through cytokines versus activating receptors has differential metabolic requirements, with activating receptor stimulation exquisitely sensitive to inhibition of glucose-driven oxidative phosphorylation (OXPHOS). IL-15 priming of NK cells can overcome metabolic requirements for NK cell effector functions in vitro and in vivo, leading to metabolic flexibility evident as the ability to efficiently function in the face of inhibition of key metabolic pathways. Our preliminary studies demonstrate activation-dependent differences in the metabolic fuels and pathways required for NK cell effector functions in vitro and in vivo that change with cytokine priming. We are interested in how cytokine priming leads to this metabolic `flexibility', with a long-term goal of applying this knowledge to strategies for NK cell therapies. This proposal presents a 5 year plan to investigate the metabolic regulation of NK cell activation. The specific aims of this proposal are to investigate: 1) metabolic pathways upregulated during cytokine priming and the effects of glucose metabolism, 2) transcription factors regulating production of cytokine transcript in primed NK cells, and 3) metabolic flexibility dependent on mTOR. We will use new inducible models with NK-specific deletion of key regulators of metabolic pathways to rigorously test our hypotheses. The studies proposed here will advance our understanding of how NK cells can be primed for metabolic flexibility and metabolic mechanisms important for NK cell effector function, with a long-term goal of optimizing strategies to target NK cells for therapy of human disease.

项目摘要 该项目的长期目标是确定NK细胞效应子功能的代谢调节 提高我们对健康和疾病中NK细胞激活的基本机制的理解。天然杀手（NK） 细胞是先天免疫淋巴细胞，是针对感染的关键第一线防御 病毒，对于肿瘤免疫监视很重要。 NK细胞通过两种机制介导其作用： 细胞因子（尤其是IFN-GAMMA）和靶细胞杀伤的产生。 NK细胞效应子功能可以是 由炎症细胞因子或种系编码的活化受体触发的，其配体 由感染和/或肿瘤细胞显示。代谢法规在许多方面起关键作用 免疫力，包括NK细胞对病毒感染的反应。我们以前证明了刺激 幼稚的，新鲜的NK细胞通过细胞因子与激活受体具有不同的代谢需求， 激活受体刺激对抑制葡萄糖驱动的氧化 磷酸化（OXPHOS）。 NK细胞的IL-15启动可以克服NK细胞的代谢需求 效应子在体外和体内功能，导致代谢灵活性证据作为有效发挥作用的能力 面对关键代谢途径的抑制。我们的初步研究表明激活依赖性 NK细胞效应子在体外和体内所需的代谢燃料和途径的差异 随着细胞因子启动的变化。我们对细胞因子启动如何导致这种代谢“灵活性”感兴趣 将这些知识应用于NK细胞疗法策略的长期目标。该提议提出了5年 计划研究NK细胞激活的代谢调节。该提议的具体目的是 研究：1）在细胞因子启动过程中上调的代谢途径和葡萄糖代谢的影响， 2）控制启动NK细胞中细胞因子转录本的转录因子和3）代谢 灵活性取决于mTOR。我们将使用新的可诱导模型以及针对NK特定删除的关键调节器的删除 代谢途径严格检验我们的假设。这里提出的研究将推动我们的 了解如何对NK细胞进行启动，以实现代谢柔韧性和代谢机制对 NK细胞效应子功能，其长期目标是优化靶向NK细胞治疗人类的策略 疾病。