Induction of the BIM short splice variant sensitizes proliferating NK cells to IL-15 withdrawal

Benedikt Jacobs, Aline Pfefferle, Dennis Clement, Axel Berg-Larsen, Michelle L. Saetersmoen, Susanne Lorenz, Merete Thune Wiiger, Jodie P. Goodridge, Karl Johan Malmberg

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7 Citations (Scopus)


Adoptive transfer of allogeneic NK cells holds great promise for cancer immunotherapy. There is a variety of protocols to expand NK cells in vitro, most of which are based on stimulation with cytokines alone or in combination with feeder cells. Although IL-15 is essential for NK cell homeostasis in vivo, it is commonly used at supraphysiological levels to induce NK cell proliferation in vitro. As a result, adoptive transfer of such IL-15–addicted NK cells is associated with cellular stress because of sudden cytokine withdrawal. In this article, we describe a dose-dependent addiction to IL-15 during in vitro expansion of human NK cells, leading to caspase-3 activation and profound cell death upon IL-15 withdrawal. NK cell addiction to IL-15 was tightly linked to the BCL-2/BIM ratio, which rapidly dropped during IL-15 withdrawal. Furthermore, we observed a proliferation-dependent induction of BIM short, a highly proapoptotic splice variant of BIM in IL-15–activated NK cells. These findings shed new light on the molecular mechanisms involved in NK cell apoptosis following cytokine withdrawal and may guide future NK cell priming strategies in a cell therapy setting.

Original languageEnglish
Pages (from-to)736-746
Number of pages11
JournalJournal of Immunology
Issue number3
Publication statusPublished - 1 Feb 2019
Externally publishedYes

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