Metabolic Regulation of Natural Killer Cell Activation

项目摘要 该项目的长期目标是确定NK细胞效应器功能的代谢调节，以 提高我们对健康和疾病中NK细胞激活的基本机制的理解。自然杀手(NK) 细胞是先天免疫淋巴细胞，是抵御感染的关键第一道防线，尤其是 病毒，并对肿瘤免疫监控很重要。NK细胞通过两种机制调节它们的作用： 产生细胞因子(尤其是干扰素-γ)和靶细胞杀伤。NK细胞效应器功能可以 由炎性细胞因子或其配体为生殖线编码的激活受体的参与而触发 由感染的和/或肿瘤细胞表现出来。代谢调节在许多方面起着关键作用 免疫，包括NK细胞对病毒感染的反应。我们之前已经证明了刺激 天真的、新鲜的NK细胞通过细胞因子与激活的受体有不同的代谢需求， 激活受体刺激对葡萄糖驱动的氧化反应的抑制非常敏感 磷酸化(OXPHOS)。IL-15激活NK细胞可克服NK细胞代谢需求 效应器在体外和体内发挥作用，导致代谢的灵活性，明显表现为有效发挥作用的能力 在关键代谢途径受到抑制的情况下。我们的初步研究表明，激活依赖于 体外和体内NK细胞效应器功能所需代谢燃料和途径的差异 随细胞因子启动而改变。我们感兴趣的是细胞因子的启动如何导致这种新陈代谢的“灵活性”， 将这一知识应用于NK细胞治疗策略的长期目标。这份建议书的期限是5年。 目的：探讨NK细胞活化的代谢调控。这项建议的具体目的是 研究：1)细胞因子启动过程中上调的代谢途径及糖代谢的影响； 2)调节NK细胞细胞因子转录产物的转录因子；3)代谢 灵活性取决于mTOR。我们将使用新的诱导模型，删除NK特异性的关键调控因子 代谢途径来严格检验我们的假说。这里提出的研究将推动我们的 了解NK细胞如何为代谢灵活性和代谢机制做好准备 NK细胞效应器功能，长期目标是优化治疗人类NK细胞的策略 疾病。

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.