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Dendritic cell-mediated NK cell activation is controlled by Jagged2-Notch interaction
- Kijima, Mika, Yamaguchi, Takeshi, Ishifune, Chieko, Maekawa, Yoichi, Koyanagi, Akemi, Yagita, Hideo, Chiba, Shigeru, Kishihara, Kenji, Shimada, Mitsuo, Yasutomo, Koji
- Proceedings of the National Academy of Sciences of the United States of America 2008 v.105 no.19 pp. 7010-7015
- autoimmune diseases, cytokines, cytotoxicity, dendritic cells, immune response, interferon-gamma, mice, natural killer cells, severe combined immunodeficiency
- 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-γ 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 γ-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.