title: Dendritic cell-mediated NK cell activation is controlled by Jagged2-Notch interaction.
abstract: Natural killer (NK) cells regulate various immune responses by exerting cytotoxic activity or secreting cytokines. The interaction of NK cells with dendritic cells (DC) contributes to NK cell-mediated antitumor or antimicrobial responses. However, the cellular and molecular mechanisms for controlling this interaction are largely unknown. Here, we show an involvement of Jagged2-Notch interaction in augmenting NK cell cytotoxicity mediated by DC. Enforced expression of Jagged2 on A20 cells (Jag2-A20 cells) suppressed their growth in vivo, which was abrogated by depleting NK cells. Moreover, Jag2-A20 cells exerted a suppression on the growth of nonmanipulated A20 cells in SCID mice in an NK-dependent manner. Consistently, coinoculation of A20 cells with DC overexpressing Jagged2 (Jag2-DC) suppressed the growth of A20 cells in mice. Stimulation of NK cells with Jagged2 directly enhanced their cytotoxicity, IFN-gamma production, and proliferation. Ligation of Notch2 on NK cells enhanced their cytotoxic activity, and Jag2-DC or CpG-treated DC-mediated NK cell cytotoxicity was suppressed by a gamma-secretase inhibitor. These results indicate that the Jagged2-Notch axis plays a crucial role in DC-mediated NK cell cytotoxicity. Furthermore, manipulation of this interaction may provide an approach to induce potent tumor immunity or to inhibit certain autoimmune diseases caused by NK cell activation.
authors.affiliation: Department of Immunology and Parasitology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima 770-8503, Japan.
authors.forename: Mika
authors.initials: M
authors.lastname: Kijima
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Chieko
authors.initials: C
authors.lastname: Ishifune
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Maekawa
authors.forename: Akemi
authors.initials: A
authors.lastname: Koyanagi
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Shigeru
authors.initials: S
authors.lastname: Chiba
authors.forename: Kenji
authors.initials: K
authors.lastname: Kishihara
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Shimada
authors.forename: Koji
authors.initials: K
authors.lastname: Yasutomo
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D017690:Cell Transplantation; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology*; D016219:Immunotherapy, Adoptive; D000072101:Jagged-2 Protein; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009369:Neoplasms / Q000276:immunology / Q000473:pathology; D011485:Protein Binding; D051880:Receptors, Notch / Q000276:immunology*; D015398:Signal Transduction
chemical_list: C490503:Jag2 protein, mouse; D000072101:Jagged-2 Protein; D008565:Membrane Proteins; D051880:Receptors, Notch