Diacylglycerol Kinase ζ Is a Target To Enhance NK Cell Function

Enhancement of NK cell function could be beneficial in treatment of a variety of tumors and infections. However, efforts to improve NK cell function by disrupting negative regulators that target proximal signaling pathways paradoxically results in hyporesponsive rather than hyperresponsive NK cells. In this study, we demonstrate that genetic deletion of diacylglycerol kinase (DGK)zeta, a negative regulator of diacylglycerol-mediated signaling, has the desired effect of enhancing NK cell function due to its distal position in the activating receptor-mediated signaling cascade. Upon stimulation through multiple activating receptors, NK cells from mice lacking DGK zeta display increased cytokine production and degranulation in an ERK-dependent manner. Additionally, they have improved cytotoxic functions against tumor cell lines. The enhancement of NK cell function by DGK zeta deficiency is NK cell-intrinsic and developmentally independent. Importantly, DGK zeta deficiency does not affect inhibitory NK cell receptor expression or function. Thus, DGK zeta knockout mice display improved missing self recognition, as evidenced by enhanced rejection of a TAP-deficient tumor in vivo. We propose that enzymes that negatively regulate distal activating receptor signaling pathways such as DGK zeta represent novel targets for augmenting the therapeutic potential of NK cells.