p35 在 NK 细胞细胞毒性与 TGF-β 介导 NK 细胞功能障碍中的关键作用

UNLABELLED: Natural killer (NK) cells are innate lymphocytes with cytotoxic activity. Understanding the factors regulating cytotoxicity is crucial for improving NK-cell adoptive therapies.

Here, we studied a previously unknown role of p35 (CDK5R1), a coactivator of cyclin-dependent kinase 5 (CDK5) in NK-cell function. p35 expression was thought to be neuronal-specific and the majority of studies are still focused on neuronal cells.

Here, we show that CDK5 and p35 are expressed in NK cells and are kinase-active. NK cells from p35 knockout mice were analyzed and showed significantly increased cytotoxicity against murine cancer cells, while they did not show any differences in cell numbers or maturation stages.

We confirmed this using human NK cells transduced with p35 short hairpin RNA (shRNA), showing similar increase in cytotoxicity against human cancer cells. Overexpression of p35 in NK cells resulted in moderate decrease in cytotoxicity, while expressing a kinase-dead mutant of CDK5 displayed increased cytotoxicity.

Together, these data suggest that p35 negatively regulates NK-cell cytotoxicity. Surprisingly, we found that TGF , a known negative regulator of NK-cell cytotoxicity, induces p35 expression in NK cells.

NK cells cultured with TGF exhibit reduced cytotoxicity, while NK cells transduced with p35 shRNA or mutant CDK5 expression exhibited partial reversal of this inhibitory effect pointing to an interesting hypothesis that p35 plays an important role in TGF -mediated NK-cell exhaustion. SIGNIFICANCE: This study reports a role for p35 in NK-cell cytotoxicity and this might help to improve NK-cell adoptive therapy.