Kern Coquillat Nicolas, Picq Louis, Hamond Ameline, Megy Pierre, Benezech Sarah, Drouillard Annabelle, Lager-Lachaud Nina, Cahoreau Edern, Moreau Marielle, Fallone Lucie, Mathieu Anne-Laure, Bellvert Floriant, Nizard Carine, Bulteau Anne-Laure, Walzer Thierry, Marçais Antoine
CIRI, Centre International de Recherche en Infectiologie, (Team Lyacts), Univ Lyon, INSERM, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Lyon, France.
LVMH Recherche, Saint Jean de Braye, France.
Nat Metab. 2025 Feb;7(2):336-347. doi: 10.1038/s42255-024-01188-4. Epub 2025 Jan 3.
Resting natural killer (NK) cells display immediate effector functions after recognizing transformed or infected cells. The environmental nutrients and metabolic requirements to sustain these functions are not fully understood. Here, we show that NK cells rely on the use of extracellular pyruvate to support effector functions, signal transduction and cell viability. Glucose-derived carbons do not generate endogenous pyruvate. Consequently, NK cells import extracellular pyruvate that is reduced to lactate to regenerate glycolytic NAD and is oxidized in the tricarboxylic acid (TCA) cycle to produce ATP. This supports serine production through phosphoglycerate dehydrogenase, a pathway required for optimal proliferation following cytokine stimulation but dispensable for effector functions. In addition, like mouse NK cells, human NK cells rely on a citrate-malate configuration of the TCA cycle that is not fed by glutamine. Moreover, supraphysiologic pyruvate concentrations dose-dependently increase the effector functions of NK cells. Overall, this study highlights the role of exogenous pyruvate in NK cell biology, providing knowledge that could be exploited to boost NK cell potential in therapeutic settings.
静息自然杀伤（NK）细胞在识别转化或感染细胞后会立即发挥效应功能。维持这些功能所需的环境营养物质和代谢需求尚未完全明确。在此，我们表明NK细胞依赖于利用细胞外丙酮酸来支持效应功能、信号转导和细胞活力。葡萄糖衍生的碳不能产生内源性丙酮酸。因此，NK细胞摄取细胞外丙酮酸，后者被还原为乳酸以再生糖酵解所需的烟酰胺腺嘌呤二核苷酸（NAD），并在线粒体三羧酸（TCA）循环中被氧化以产生三磷酸腺苷（ATP）。这通过磷酸甘油酸脱氢酶支持丝氨酸的产生，这是细胞因子刺激后最佳增殖所需的一条途径，但对效应功能而言并非必需。此外，与小鼠NK细胞一样，人NK细胞依赖于不由谷氨酰胺供能的TCA循环的柠檬酸-苹果酸构型。而且，超生理浓度的丙酮酸剂量依赖性地增强NK细胞的效应功能。总体而言，本研究突出了外源性丙酮酸在NK细胞生物学中的作用，提供了可用于在治疗环境中增强NK细胞潜能的知识。
