Dendritic cell-mediated NK cell activation is controlled by Jagged2-Notch interaction
Dendritic cell-mediated NK cell activation is controlled by Jagged2-Notch interaction
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DOI：
10.1073/pnas.0709919105
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发表时间：
2008-05-13
影响因子：
11.1
通讯作者：
Yasutomo, Koji
中科院分区：
文献类型：
--
作者：
Kijima, Mika;Yamaguchi, Takeshi;Yasutomo, Koji
自然杀伤(NK)细胞通过发挥细胞毒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微生物反应。然而，控制这种相互作用的细胞和分子机制在很大程度上是未知的。在这里，我们展示了Jagged2-Notch相互作用在增强DC介导的NK细胞杀伤作用中的作用。在A20细胞(Jag2-A20细胞)上强制表达Jagged2可抑制其体内生长，这种抑制作用可通过耗尽NK细胞而被取消。此外，Jag2-A20细胞以NK依赖的方式抑制SCID小鼠未经处理的A20细胞的生长。A20细胞与高表达Jagged2的DC(Jag2-DC)共接种可抑制小鼠A20细胞的生长。Jagged2对NK细胞的刺激直接增强了其细胞毒作用、干扰素-γ的产生和增殖。结扎Notch2可增强NK细胞的细胞毒活性，而Jag2-DC或CpG诱导的DC介导的NK细胞毒活性可被γ-分泌酶抑制剂抑制。这些结果表明Jagged2-Notch轴在DC介导的NK细胞杀伤中起重要作用。此外，操纵这种相互作用可能提供一种方法来诱导强大的肿瘤免疫或抑制某些由NK细胞激活引起的自身免疫性疾病。
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.