Glycolytic requirement for NK cell cytotoxicity and cytomegalovirus control
Glycolytic requirement for NK cell cytotoxicity and cytomegalovirus control
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DOI：
10.1172/jci.insight.95128
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发表时间：
2017-12-07
期刊：
影响因子：
8
通讯作者：
Cooper, Megan A.
中科院分区：
文献类型：
--
作者：
Mah, Annelise Y.;Rashidi, Armin;Cooper, Megan A.
NK细胞活化已被证明是在体外代谢调节；然而，代谢在体内NK细胞对感染反应中的作用尚不清楚。我们研究了糖酵解在小鼠巨细胞病毒（MCMV）感染期间NK细胞功能中的作用，以及IL-15在巨细胞病毒感染期间启动NK细胞的能力。葡萄糖代谢抑制剂2-脱氧-d -葡萄糖（2DG）在体外引发后对小鼠和人NK细胞的细胞毒性均有损害。同样，用2DG处理的mcmv感染小鼠体内对nk特异性靶点的清除受损，这与C57BL/6背景下更高的病毒负担和对感染的易感性有关。已知IL-15启动会改变NK细胞的代谢和激活的代谢需求。用IL-15超级激动剂ALT-803以nk依赖的方式将小鼠从其他致命感染中拯救出来。与此一致的是，用ALT-803治疗造血细胞移植后复发性巨细胞病毒再激活的患者与病毒血症的清除有关。这些研究表明NK细胞介导的病毒感染控制需要葡萄糖代谢，而体内IL-15治疗可以减少这一需求，并可能作为一种有效的抗病毒治疗。
NK cell activation has been shown to be metabolically regulated in vitro; however, the role of metabolism during in vivo NK cell responses to infection is unknown. We examined the role of glycolysis in NK cell function during murine cytomegalovirus (MCMV) infection and the ability of IL-15 to prime NK cells during CMV infection. The glucose metabolism inhibitor 2-deoxy-D-glucose (2DG) impaired both mouse and human NK cell cytotoxicity following priming in vitro. Similarly, MCMV-infected mice treated with 2DG had impaired clearance of NK-specific targets in vivo, which was associated with higher viral burden and susceptibility to infection on the C57BL/6 background. IL-15 priming is known to alter NK cell metabolism and metabolic requirements for activation. Treatment with the IL-15 superagonist ALT-803 rescued mice from otherwise lethal infection in an NK-dependent manner. Consistent with this, treatment of a patient with ALT-803 for recurrent CMV reactivation after hematopoietic cell transplant was associated with clearance of viremia. These studies demonstrate that NK cell-mediated control of viral infection requires glucose metabolism and that IL-15 treatment in vivo can reduce this requirement and may be effective as an antiviral therapy.