NK cells switch from granzyme B to death receptor-mediated cytotoxicity during serial killing
NK cells switch from granzyme B to death receptor-mediated cytotoxicity during serial killing
复制标题
DOI：
10.1084/jem.20181454
复制
发表时间：
2019-09-01
影响因子：
15.3
通讯作者：
Watzl, Carsten
中科院分区：
文献类型：
--
作者：
Prager, Isabel;Liesche, Clarissa;Watzl, Carsten
NK细胞通过释放含有颗粒酶B（Grz B）的细胞毒性颗粒或通过接合启动半胱天冬酶级联的死亡受体来消除病毒感染的细胞和肿瘤细胞。两种细胞死亡途径之间的协调相互作用仍然不清楚。在这里，我们同时测量与人NK细胞接触后肿瘤细胞中GrzB和caspase-8的活性。我们观察到NK细胞从在其第一次杀伤事件中诱导快速GrzB介导的细胞死亡转变为在随后的肿瘤细胞遭遇期间诱导缓慢的死亡受体介导的杀伤。随着时间的推移，靶细胞接触减少了NK细胞中的细胞内GrzB和穿孔素，并增加了表面-CD 95 L，显示了细胞毒性途径的转换是如何控制的。在没有穿孔素的情况下，NK细胞不能执行GrzB介导的连续杀伤，并且仅通过死亡受体杀死一次。相比之下，肿瘤靶点上CD 95的缺失并不损害GrzB介导的连环杀伤。这表明GrzB和死亡受体介导的细胞毒性在NK细胞连续杀伤期间受到差异调节。
NK cells eliminate virus-infected and tumor cells by releasing cytotoxic granules containing granzyme B (GrzB) or by engaging death receptors that initiate caspase cascades. The orchestrated interplay between both cell death pathways remains poorly defined. Here we simultaneously measure the activities of GrzB and caspase-8 in tumor cells upon contact with human NK cells. We observed that NK cells switch from inducing a fast GrzB-mediated cell death in their first killing events to a slow death receptor-mediated killing during subsequent tumor cell encounters. Target cell contact reduced intracellular GrzB and perforin and increased surface-CD95L in NK cells over time, showing how the switch in cytotoxicity pathways is controlled. Without perforin, NK cells were unable to perform GrzB-mediated serial killing and only killed once via death receptors. In contrast, the absence of CD95 on tumor targets did not impair GrzB-mediated serial killing. This demonstrates that GrzB and death receptor-mediated cytotoxicity are differentially regulated during NK cell serial killing.