METABOLIC REGULATION OF NATURAL KILLER CELL ACTIVATION

项目摘要 该项目的长期目标是确定NK细胞效应功能的代谢调节， 提高我们对健康和疾病中NK细胞活化的基本机制的理解。自然杀伤细胞（NK） 细胞是先天免疫淋巴细胞，作为对抗感染的关键第一线防御，特别是 病毒，并且对于肿瘤免疫监视是重要的。NK细胞通过两种机制介导其作用： 产生细胞因子（特别是IFN-γ）和靶细胞杀伤。NK细胞效应子功能可以是 由炎性细胞因子或生殖细胞编码的激活受体的参与触发， 被感染和/或肿瘤细胞展示。代谢调节在许多方面起着关键作用， 免疫，包括激活和记忆T细胞的产生。有两种主要的代谢 产生细胞内能量（ATP）、糖酵解和线粒体氧化磷酸化的途径 （OXPHOS）。驱动细胞代谢的燃料（例如，葡萄糖、脂肪酸）在许多疾病中发生改变 状态和代谢途径是候选药物的有希望的靶点。虽然NK细胞激活的触发因素 和随后的NK细胞效应器反应已经得到了很好的表征，NK细胞所需的代谢燃料 细胞功能反应和NK细胞活化的代谢调节的概念在很大程度上未被探索。 我们的初步数据表明，OXPHOS和糖酵解都是NK细胞活化所必需的， NK细胞的细胞因子激活受体，但NK细胞的细胞因子刺激不需要特定的代谢途径。 在用IL-15引发后，NK细胞活化的代谢要求改变，并且NK细胞具有 保留了对受体活化和代谢抑制的响应功能。该提案提出了一个5年 计划研究NK细胞活化的代谢调节。我们假设， 细胞代谢将影响体内NK细胞功能。本提案的具体目的是调查：1） NK细胞的受体刺激依赖于代谢的机制以及IL-15如何引发 改变了这一点，2）NK细胞分化和体内病毒感染反应的代谢要求 使用基因靶向小鼠模型。这些研究将提供对代谢途径的深入了解， 控制NK细胞活化，并靶向患者的潜在途径，以增强NK细胞功能。

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 the activation and generation of memory T cells. There are two primary metabolic pathways for generating intracellular energy (ATP), glycolysis and mitochondrial oxidative phosphorylation (OXPHOS). The fuels that drive cellular metabolism (e.g., glucose, fatty acids) are altered in many disease states, and metabolic pathways are promising targets for drug candidates. While triggers of NK cell activation and subsequent NK cell effector responses have been well-characterized, the metabolic fuels required for NK cell functional responses, and the concept of metabolic regulation of NK cell activation are largely unexplored. Our preliminary data demonstrates that both OXPHOS and glycolysis are required for activation of NK cells by activating receptors, but that cytokine stimulation of NK cells does not require a specific metabolic pathway. Following priming with IL-15, the metabolic requirements for NK cell activation are altered, and NK cells have preserved function in response to receptor activation with metabolic inhibition. This proposal presents a 5 year plan to investigate the metabolic regulation of NK cell activation. We hypothesize that alterations of intrinsic cellular metabolism will impact NK cell function in vivo. The specific aims of this proposal are to investigate: 1) the mechanisms by which receptor stimulation of NK cells is dependent on metabolism and how IL-15 priming alters this, and 2) the metabolic requirements for NK cell differentiation and response to viral infection in vivo using genetically targeted mouse models. These studies will provide insight into metabolic pathways that control NK cell activation, and potential pathways to target in patients to enhance NK cell function.