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NK cells switch from granzyme B to death receptor–mediated cytotoxicity during serial killing
Department for Immunology, Leibniz Research Centre for Working Environment and Human Factors at TU Dortmund, Dortmund, Germany.
Division of Theoretical Bioinformatics, German Cancer Research Center and BioQuant Center, Heidelberg, Germany.
KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
Department for Immunology, Leibniz Research Centre for Working Environment and Human Factors at TU Dortmund, Dortmund, Germany.
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2019 (English)In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 7, no 9, p. 2113-2127Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2019. Vol. 7, no 9, p. 2113-2127
National Category
Immunology in the medical area
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URN: urn:nbn:se:kth:diva-256334DOI: 10.1084/jem.20181454ISI: 000484027100013PubMedID: 31270246Scopus ID: 2-s2.0-85071782240OAI: oai:DiVA.org:kth-256334DiVA, id: diva2:1344894
Note

QC 20190822

Available from: 2019-08-22 Created: 2019-08-22 Last updated: 2019-10-28Bibliographically approved

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van Ooijen, HannaVerron, QuentinSandström, NiklasÖnfelt, Björn

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