The purinergic receptor P2RX7 directs metabolic fitness of long-lived memory CD8+ T cells,Nature

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The purinergic receptor P2RX7 directs metabolic fitness of long-lived memory CD8+ T cells
Nature ( IF 50.5 ) Pub Date : 2018-07-01 , DOI: 10.1038/s41586-018-0282-0
Henrique Borges da Silva _{1,

2} , Lalit K Beura _{1,

3} , Haiguang Wang _{1,

2} , Eric A Hanse _{1,

2} , Reshma Gore ₄ , Milcah C Scott _{1,

3} , Daniel A Walsh _{1,

2} , Katharine E Block _{1,

2} , Raissa Fonseca _{1,

3} , Yan Yan _{1,

2} , Keli L Hippen _{1,

5} , Bruce R Blazar _{1,

5} , David Masopust _{1,

3} , Ameeta Kelekar _{1,

2} , Lucy Vulchanova ₄ , Kristin A Hogquist _{1,

2} , Stephen C Jameson _{1,

2}

Affiliation

Extracellular ATP (eATP) is an ancient ‘danger signal’ used by eukaryotes to detect cellular damage1. In mice and humans, the release of eATP during inflammation or injury stimulates both innate immune activation and chronic pain through the purinergic receptor P2RX72–4. It is unclear, however, whether this pathway influences the generation of immunological memory, a hallmark of the adaptive immune system that constitutes the basis of vaccines and protective immunity against re-infection5,6. Here we show that P2RX7 is required for the establishment, maintenance and functionality of long-lived central and tissue-resident memory CD8+ T cell populations in mice. By contrast, P2RX7 is not required for the generation of short-lived effector CD8+ T cells. Mechanistically, P2RX7 promotes mitochondrial homeostasis and metabolic function in differentiating memory CD8+ T cells, at least in part by inducing AMP-activated protein kinase. Pharmacological inhibitors of P2RX7 provoked dysregulated metabolism and differentiation of activated mouse and human CD8+ T cells in vitro, and transient P2RX7 blockade in vivo ameliorated neuropathic pain but also compromised production of CD8+ memory T cells. These findings show that activation of P2RX7 by eATP provides a common currency that both alerts the nervous and immune system to tissue damage, and promotes the metabolic fitness and survival of the most durable and functionally relevant memory CD8+ T cell populations.Activation of P2RX7 receptors by extracellular ATP is required for the generation, maintenance and function of central and tissue-resident CD8+ memory T cells.

中文翻译：

嘌呤能受体 P2RX7 指导长寿命记忆 CD8+ T 细胞的代谢适应性

细胞外 ATP (eATP) 是真核生物用来检测细胞损伤的古老“危险信号”1。在小鼠和人类中，炎症或损伤期间 eATP 的释放通过嘌呤能受体 P2RX72-4 刺激先天免疫激活和慢性疼痛。然而，尚不清楚该途径是否影响免疫记忆的产生，这是适应性免疫系统的标志，构成疫苗和针对再感染的保护性免疫的基础5,6。在这里，我们表明 P2RX7 是小鼠中长寿命中枢和组织驻留记忆 CD8+ T 细胞群的建立、维持和功能所必需的。相比之下，短寿命效应 CD8+ T 细胞的产生不需要 P2RX7。从机制上讲，P2RX7 在分化记忆 CD8+ T 细胞中促进线粒体稳态和代谢功能，至少部分是通过诱导 AMP 活化蛋白激酶。P2RX7 的药理学抑制剂在体外引起活化的小鼠和人类 CD8+ T 细胞的代谢和分化失调，体内瞬时 P2RX7 阻断可改善神经性疼痛，但也会损害 CD8+ 记忆 T 细胞的产生。这些发现表明，eATP 对 P2RX7 的激活提供了一种共同的货币，既可以提醒神经系统和免疫系统注意组织损伤，又可以促进最持久和功能相关的记忆 CD8+ T 细胞群的代谢适应性和存活。 P2RX7 受体的激活通过细胞外 ATP 是中枢和组织驻留 CD8+ 记忆 T 细胞的产生、维持和功能所必需的。

更新日期：2018-07-01

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