title: Diacylglycerol Kinase ζ Is a Target To Enhance NK Cell Function.
abstract: 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)ζ, 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 DGKζ 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 DGKζ deficiency is NK cell-intrinsic and developmentally independent. Importantly, DGKζ deficiency does not affect inhibitory NK cell receptor expression or function. Thus, DGKζ 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 DGKζ represent novel targets for augmenting the therapeutic potential of NK cells.
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Enjun
authors.identifier: 0000-0003-1511-7511
authors.initials: E
authors.lastname: Yang
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Brenal K
authors.identifier: 0000-0003-1275-0434
authors.initials: BK
authors.lastname: Singh
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Amanda M Schmidt
authors.identifier: 0000-0001-9031-0595
authors.initials: AM
authors.lastname: Paustian
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104 taku.kambayashi@uphs.upenn.edu.
authors.forename: Taku
authors.initials: T
authors.lastname: Kambayashi
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002469:Cell Separation; D019852:Diacylglycerol Kinase / Q000276:immunology*; D005434:Flow Cytometry; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D019852:Diacylglycerol Kinase; C512480:diacylglycerol kinase zeta, mouse