期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 216, 期 9, 页码 2113-2127出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20181454
关键词
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资金
- Initiative and Networking Fund of the Helmholtz Association within the Helmholtz Alliance on Systems Biology/SBCancer
- Deutsche Forschungsgemeinschaft (DFG) [WA-1552/8-1]
- Swedish Foundation for Strategic Research [SBE13-0092]
- Swedish Cancer Foundation [2015-05268]
- Swedish Research Council [CAN 2016/730]
- Swedish Research Council [2015-05268] Funding Source: Swedish Research Council
- Swedish Foundation for Strategic Research (SSF) [SBE13-0092] Funding Source: Swedish Foundation for Strategic Research (SSF)
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.
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