Kijima Mika, Yamaguchi Takeshi, Ishifune Chieko, Maekawa Yoichi, Koyanagi Akemi, Yagita Hideo, Chiba Shigeru, Kishihara Kenji, Shimada Mitsuo, Yasutomo Koji
Department of Immunology and Parasitology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima 770-8503, Japan.
Proc Natl Acad Sci U S A. 2008 May 13;105(19):7010-5. doi: 10.1073/pnas.0709919105. Epub 2008 May 5.
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.
自然杀伤（NK）细胞通过发挥细胞毒性活性或分泌细胞因子来调节各种免疫反应。NK细胞与树突状细胞（DC）的相互作用有助于NK细胞介导的抗肿瘤或抗菌反应。然而，控制这种相互作用的细胞和分子机制在很大程度上尚不清楚。在此，我们展示了锯齿状蛋白2-Notch相互作用在增强DC介导的NK细胞细胞毒性中的作用。在A20细胞（Jag2-A20细胞）上强制表达锯齿状蛋白2可抑制其在体内的生长，而通过耗尽NK细胞可消除这种抑制作用。此外，Jag2-A20细胞以NK依赖的方式对SCID小鼠中未处理的A20细胞的生长产生抑制作用。同样，将A20细胞与过表达锯齿状蛋白2的DC（Jag2-DC）共同接种可抑制小鼠中A20细胞的生长。用锯齿状蛋白2直接刺激NK细胞可增强其细胞毒性、γ干扰素产生和增殖。NK细胞上Notch2的结合增强了其细胞毒性活性，并且γ-分泌酶抑制剂可抑制Jag2-DC或经CpG处理的DC介导的NK细胞细胞毒性。这些结果表明，锯齿状蛋白2-Notch轴在DC介导的NK细胞细胞毒性中起关键作用。此外，操纵这种相互作用可能提供一种诱导强效肿瘤免疫或抑制由NK细胞激活引起的某些自身免疫性疾病的方法。
