Induction of the BIM Short Splice Variant Sensitizes Proliferating NK Cells to IL-15 Withdrawal

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 supra-physiological 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 due to sudden cytokine withdrawal. Here, we describe a dose-dependent addiction to IL-15 during in vitro expansion, 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 (BIM S), a highly pro-apoptotic 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.