The role of Cdk5/p35 kinase activity in natural killer cell cytotoxicity

Abstract

Abstract Natural killer (NK) cells and T cells are immune cells with cytotoxic function, but while the distinct role of Cyclin-dependent kinase 5 (Cdk5) in the activation and effector function of T cells has been explored, its role in NK cells is unknown. Here, we show that both Cdk5 and its obligatory co-activator p35 protein are expressed in NK cells. We also detect Cdk5 kinase activity in NK cells, and kinase inhibition via p35 shRNA results in increased NK cell cytotoxicity. Overexpression of p35, which increases Cdk5 kinase activity, results in decreased NK cell cytotoxicity. Exogenous expression of a kinase-dead Cdk5 mutant that is still capable of binding p35 also increases NK cell cytotoxicity. Meanwhile, p35 knockout mouse NK cells exhibit significantly higher cytotoxicity against murine melanoma cells compared to wild-type NK cells. Based on our preliminary data, we conclude that Cdk5/p35 kinase activity negatively regulates NK cell cytotoxicity, with implications for the potential improvement of NK cell-based cancer immunotherapies. Supported by grants from the NIH (R21 CA246194, T32 GM007250) and the St. Baldrick's Scholar Award.