The Energy Sensor AMPK Regulates T Cell Metabolic Adaptation and Effector Responses In Vivo
The Energy Sensor AMPK Regulates T Cell Metabolic Adaptation and Effector Responses In Vivo
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DOI：
10.1016/j.immuni.2014.12.030
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发表时间：
2015-01-20
期刊：
影响因子：
32.4
通讯作者：
Jones, Russell G.
中科院分区：
文献类型：
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作者：
Blagih, Julianna;Coulombe, Francois;Jones, Russell G.
初始T细胞经历代谢重编程以支持效应T细胞功能所增加的能量和生物合成需求。然而，营养物质的可利用性如何影响T细胞代谢和功能仍知之甚少。在此我们报道了效应T细胞代谢对营养物质可利用性变化的可塑性。研究发现，活化的T细胞具有一个由能量传感器AMP活化蛋白激酶（AMPK）控制的葡萄糖敏感代谢检查点，该检查点调节mRNA翻译以及谷氨酰胺依赖性线粒体代谢，以维持T细胞的生物能量学和生存能力。缺乏AMPKα1的T细胞在体外葡萄糖受限或体内病原体攻击时，线粒体生物能量学和细胞ATP降低。最后，我们证明AMPKα1对辅助性T细胞1（Th1）和Th17细胞的发育以及体内对病毒和细菌感染的初始T细胞反应至关重要。我们的数据强调了AMPK依赖性的代谢稳态调节是T细胞介导的适应性免疫的关键调节因素。
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 AMPK alpha 1 displayed reduced mitochondrial bioenergetics and cellular ATP in response to glucose limitation in vitro or pathogenic challenge in vivo. Finally, we demonstrated that AMPKa1 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.