Goodman Cancer Research Centre, McGill University, Montreal, QC, H3G 1Y6, Canada; Department of Physiology, McGill University, Montreal, QC, H3G 1Y6, Canada.
Departments of Medicine, Microbiology & Immunology, and Pathology, McGill International TB Centre, McGill University Health Centre and Research Institute, Meakins-Christie Laboratories, Montreal, QC, H2X 2P2, Canada.
Immunity. 2015 Jan 20;42(1):41-54. doi: 10.1016/j.immuni.2014.12.030. Epub 2015 Jan 2.
Naive T cells undergo metabolic reprogramming to support the increased energetic and biosynthetic demands of effector T cell function. However, how nutrient availability influences T cell metabolism and function remains poorly understood. Here we report plasticity in effector T cell metabolism in response to changing nutrient availability. Activated T cells were found to possess a glucose-sensitive metabolic checkpoint controlled by the energy sensor AMP-activated protein kinase (AMPK) that regulated mRNA translation and glutamine-dependent mitochondrial metabolism to maintain T cell bioenergetics and viability. T cells lacking AMPKα1 displayed reduced mitochondrial bioenergetics and cellular ATP in response to glucose limitation in vitro or pathogenic challenge in vivo. Finally, we demonstrated that AMPKα1 is essential for T helper 1 (Th1) and Th17 cell development and primary T cell responses to viral and bacterial infections in vivo. Our data highlight AMPK-dependent regulation of metabolic homeostasis as a key regulator of T cell-mediated adaptive immunity.
幼稚 T 细胞经历代谢重编程，以支持效应 T 细胞功能的能量和生物合成需求增加。然而，营养物质可用性如何影响 T 细胞代谢和功能仍知之甚少。在这里，我们报告了效应 T 细胞代谢对营养物质可用性变化的可塑性。研究发现，激活的 T 细胞具有葡萄糖敏感的代谢检查点，由能量传感器 AMP 激活的蛋白激酶 (AMPK) 控制，该检查点调节 mRNA 翻译和谷氨酰胺依赖性线粒体代谢，以维持 T 细胞的生物能量和活力。在体外葡萄糖限制或体内致病性挑战时，缺乏 AMPKα1 的 T 细胞表现出线粒体生物能量和细胞内 ATP 减少。最后，我们证明 AMPKα1 对于 T 辅助 1 (Th1) 和 Th17 细胞的发育以及体内 T 细胞对病毒和细菌感染的初始反应是必不可少的。我们的数据强调了 AMPK 依赖性代谢平衡的调节是 T 细胞介导的适应性免疫的关键调节剂。
