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J Exp Med. 2019 Sep 2;216(9):2113-2127. doi: 10.1084/jem.20181454. Epub 2019 Jul 3.

NK cells switch from granzyme B to death receptor-mediated cytotoxicity during serial killing.

Author information

1
Department for Immunology, Leibniz Research Centre for Working Environment and Human Factors at TU Dortmund, Dortmund, Germany.
2
Division of Theoretical Bioinformatics, German Cancer Research Center and BioQuant Center, Heidelberg, Germany.
3
Department of Applied Physics, Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden.
4
Division of Theoretical Bioinformatics, German Cancer Research Center and BioQuant Center, Heidelberg, Germany jbeaudouin@googlemail.com.
5
Department of Applied Physics, Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden onfelt@kth.se.
6
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
7
Department for Immunology, Leibniz Research Centre for Working Environment and Human Factors at TU Dortmund, Dortmund, Germany watzl@ifado.de.
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Contributed equally

Abstract

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.

PMID:
31270246
PMCID:
PMC6719417
[Available on 2020-03-02]
DOI:
10.1084/jem.20181454

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