PDF(Pubmed)
Abstract：
UNASSIGNED: Unique metabolic requirements accompany the development and functional fates of immune cells. How cellular metabolism is important in natural killer (NK) cells and their memory-like differentiation in bacterial infections remains elusive.
UNASSIGNED: Here, we utilise our established NK cell memory assay to investigate the metabolic requirement for memory-like NK cell formation and function in response to the Gram-negative intracellular bacteria Burkholderia pseudomallei (BP), the causative agent of melioidosis.
UNASSIGNED: We demonstrate that CD160+ memory-like NK cells upon BP stimulation upregulate glucose and amino acid transporters in a cohort of recovered melioidosis patients which is maintained at least 3-month post-hospital admission. Using an in vitro assay, human BP-specific CD160+ memory-like NK cells show metabolic priming including increased expression of glucose and amino acid transporters with elevated glucose uptake, increased mTOR activation and mitochondrial membrane potential upon BP re-stimulation. Antigen-specific and cytokine-induced IFN-γ production of this memory-like NK cell subset are highly dependent on oxidative phosphorylation (OXPHOS) with some dependency on glycolysis, whereas the formation of CD160+ memory-like NK cells in vitro is dependent on fatty acid oxidation and OXPHOS and further increased by metformin.
UNASSIGNED: This study reveals the link between metabolism and cellular function of memory-like NK cells, which can be exploited for vaccine design and for monitoring protection against Gram-negative bacterial infection.
UNASSIGNED: Here, we utilise our established NK cell memory assay to investigate the metabolic requirement for memory-like NK cell formation and function in response to the Gram-negative intracellular bacteria Burkholderia pseudomallei (BP), the causative agent of melioidosis.
UNASSIGNED: We demonstrate that CD160+ memory-like NK cells upon BP stimulation upregulate glucose and amino acid transporters in a cohort of recovered melioidosis patients which is maintained at least 3-month post-hospital admission. Using an in vitro assay, human BP-specific CD160+ memory-like NK cells show metabolic priming including increased expression of glucose and amino acid transporters with elevated glucose uptake, increased mTOR activation and mitochondrial membrane potential upon BP re-stimulation. Antigen-specific and cytokine-induced IFN-γ production of this memory-like NK cell subset are highly dependent on oxidative phosphorylation (OXPHOS) with some dependency on glycolysis, whereas the formation of CD160+ memory-like NK cells in vitro is dependent on fatty acid oxidation and OXPHOS and further increased by metformin.
UNASSIGNED: This study reveals the link between metabolism and cellular function of memory-like NK cells, which can be exploited for vaccine design and for monitoring protection against Gram-negative bacterial infection.
摘要：
■免疫细胞的发育和功能命运伴随着独特的代谢要求。细胞代谢在自然杀伤（NK）细胞中的重要性以及它们在细菌感染中的记忆样分化仍然难以捉摸。
■这里，我们利用我们建立的NK细胞记忆试验来研究记忆样NK细胞形成和功能的代谢需求，以响应革兰氏阴性细胞内细菌Burkholderiapseudomallei（BP），类鼻窦病的病原体。
■我们证明了CD160+记忆样NK细胞在BP刺激后上调了一组恢复的类石斑病患者的葡萄糖和氨基酸转运蛋白，这些患者在入院后至少维持了3个月。使用体外测定法，人BP特异性CD160+记忆样NK细胞表现出代谢启动，包括葡萄糖和氨基酸转运蛋白表达增加，葡萄糖摄取升高，BP再刺激后mTOR激活和线粒体膜电位增加。这种记忆样NK细胞亚群的抗原特异性和细胞因子诱导的IFN-γ产生高度依赖于氧化磷酸化（OXPHOS），在一定程度上依赖于糖酵解，而体外CD160+记忆样NK细胞的形成依赖于脂肪酸氧化和OXPHOS，并通过二甲双胍进一步增加。
■这项研究揭示了类似记忆的NK细胞的代谢和细胞功能之间的联系，可用于疫苗设计和监测针对革兰氏阴性细菌感染的保护。
■这里，我们利用我们建立的NK细胞记忆试验来研究记忆样NK细胞形成和功能的代谢需求，以响应革兰氏阴性细胞内细菌Burkholderiapseudomallei（BP），类鼻窦病的病原体。
■我们证明了CD160+记忆样NK细胞在BP刺激后上调了一组恢复的类石斑病患者的葡萄糖和氨基酸转运蛋白，这些患者在入院后至少维持了3个月。使用体外测定法，人BP特异性CD160+记忆样NK细胞表现出代谢启动，包括葡萄糖和氨基酸转运蛋白表达增加，葡萄糖摄取升高，BP再刺激后mTOR激活和线粒体膜电位增加。这种记忆样NK细胞亚群的抗原特异性和细胞因子诱导的IFN-γ产生高度依赖于氧化磷酸化（OXPHOS），在一定程度上依赖于糖酵解，而体外CD160+记忆样NK细胞的形成依赖于脂肪酸氧化和OXPHOS，并通过二甲双胍进一步增加。
■这项研究揭示了类似记忆的NK细胞的代谢和细胞功能之间的联系，可用于疫苗设计和监测针对革兰氏阴性细菌感染的保护。
