Cytokine-enhanced cytolytic activity of exosomes from NK Cells.

Autor: Enomoto Y; Laboratory of Molecular Immunology, Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892-1674, USA., Li P; Laboratory of Molecular Immunology, Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892-1674, USA., Jenkins LM; Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, 20892, USA., Anastasakis D; RNA Molecular Biology Group, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD, 20892, USA., Lyons GC; Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, 20892, USA., Hafner M; RNA Molecular Biology Group, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD, 20892, USA., Leonard WJ; Laboratory of Molecular Immunology, Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892-1674, USA. leonardw@nhlbi.nih.gov.
Jazyk: angličtina
Zdroj: Cancer gene therapy [Cancer Gene Ther] 2022 Jun; Vol. 29 (6), pp. 734-749. Date of Electronic Publication: 2021 Jul 27.
DOI: 10.1038/s41417-021-00352-2
Abstrakt: Natural killer (NK) cells play key roles in immune surveillance against tumors and viral infection. NK cells distinguish abnormal cells from healthy cells by cell-cell interaction with cell surface proteins and then attack target cells via multiple mechanisms. In addition, extracellular vesicles (EVs) derived from NK cells (NK-EVs), including exosomes, possess cytotoxic capacity against tumor cells, but their characteristics and regulation by cytokines remain unknown. Here, we report that EVs derived from human NK-92 cells stimulated with IL-15 + IL-21 show enhanced cytotoxic capacity against tumor cells. Major cytolytic granules, granzyme B and granzyme H, are enriched by IL-15 + IL-21 stimulation in NK-EVs; however, knockout experiments reveal those cytolytic granules are independent of enhanced cytotoxic capacity. To find out the key molecules, mass spectrometry analyses were performed with different cytokine conditions, no cytokine, IL-15, IL-21, or IL-15 + IL-21. We then found that CD226 (DNAM-1) on NK-EVs is enriched by IL-15 + IL-21 stimulation and that blocking antibodies against CD226 reduced the cytolytic activity of NK-EVs. We also show NK-EVs are taken up by target cells via macropinocytosis. Collectively, our findings elucidate the novel properties of NK-EVs and the mechanism of their incorporation into target cells.
(© 2021. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2021.)
Databáze: MEDLINE
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