Establishment of the system to control T lymphocyte functions using Notch ligands

利用Notch配体控制T淋巴细胞功能的系统的建立

• 批准号: 18590474
• 负责人: KISHIHARA Kenji
• 金额: $ 2.53万
• 依托单位: The University of Tokushima
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590474/
• 关键词: Notch; Notch ligands; T lymphocyte; immunoregulation; Lunatic fringe; Glycosylation; NK cell; リンパ球; 抗腫瘍免疫; 機能制御

In this research project, the first attempt to establish the system to control T lymphocyte function was done using tail-truncated Notch ligands because such mutanted molecules modulate fruit fly development. Unfortunately, the attempt was failed despite various constructs of tail-truncated Notch ligand genes were produced and then assayed. Nextly, the following two projects were performed : (1) to study a role of lunatic fringe, which modulate Notch-signaling by glycosylation of Notch molecules, in T cell development and (2) to examine effects of Notch/Notch ligands on NK cell activation and fuction.(1)Overexpression of Lfng in Jurkat T cells strengthened Notch signaling, indicating that Lfng is a positive regulator for Notch signaling in T cells. The enforced expression of Lfng in thymocytes enhanced the development of immature CD8SP cells but decreased mature CD4SP and CD8SP cells. In contrast, the down-regulation of Lfng in thymocytes suppressed DP cell development due to the defec … More tive diffentiation in DN cell stage. The overexpression of Lfng in fetal liver-derived hemopoietic stem cells enhanced T cell development, whereas its down-regulation suppressed it. These results suggest that the high expression of Ling in DN cells contributes to enhance T cell differentiation through strengthening Notch signaling.(2)Enforced expression of Jagged2 on A20 tumor cells suppressed their growth in vivo, which was abrogated by depleting NK cells. Consistently, coinoculation of A20 cells with DC overexpressing Jagged2suppressed 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 MC cells enhanced their cytotoxic activity, which was suppressed by a gamma-secretase inhibitor. These results indicate that the Jagged2-Notch axis plays a crucial role in DC-mediated MC cell cytotoxicity. Furthermore, manipulation of this interaction may provide an approach to induce potent tumor immunity.sp Less

在该研究项目中，首次尝试使用尾部截短的Notch配体建立控制T淋巴细胞功能的系统，因为这种突变分子调节果蝇发育。不幸的是，尽管产生了尾截短的Notch配体基因的各种构建体，然后进行了测定，但该尝试失败了。接下来，进行了以下两个项目：（1）研究通过Notch分子的糖基化调节Notch信号传导的Lunatic fringe在T细胞发育中的作用;（2）研究Notch/Notch配体对NK细胞活化和功能的影响。（1）Lfng在Jurkat T细胞中的过表达增强了Notch信号传导，表明Lfng是T细胞中Notch信号传导的正调节剂。Lfng在胸腺细胞中的强表达促进了未成熟CD 8 SP细胞的发育，但降低了成熟CD 4SP和CD 8 SP细胞的发育。相反，胸腺细胞中Lfng的下调抑制了DP细胞的发育，这是由于胸腺细胞中Lfng的缺陷导致的。 ...更多信息 DN细胞期分化明显。Lfng在胎肝造血干细胞中的过表达促进T细胞的发育，而其下调则抑制T细胞的发育，提示Ling在DN细胞中的高表达可能通过增强Notch信号通路促进T细胞的分化。（2）Jagged 2在A20肿瘤细胞上的强表达抑制其体内生长，这通过消耗NK细胞而被消除。结论：过表达Jagged 2的DC与A20细胞共接种可抑制A20细胞的生长。用Jagged 2刺激NK细胞直接增强其细胞毒性、IFN-γ产生和增殖。Notch 2在MC细胞上的连接增强了它们的细胞毒活性，这被γ-分泌酶抑制剂抑制。这些结果表明，锯齿状2-Notch轴在DC介导的MC细胞毒性中起着至关重要的作用。此外，操纵这种相互作用可能提供一种诱导有效肿瘤免疫的方法。

项目成果

Lunatic fringe controls T cell differentiation through modulating notch signaling

Lunatic fring通过调节Notch信号传导控制T细胞分化

• 发表时间: 2006
• 期刊: The Journal of Immunology 177
• 作者: 九十九伸-

Jagged2によるNK細胞活性化制御の解析

Jagged2对NK细胞激活的调控分析

• 发表时间: 2007
• 作者: Kaneda H;Takeda K;Ota T;Kaduka Y;Akiba H;Ikarashi Y;Wakasugi H;Kronenberg M;Kinoshita K;Yagita H;Okumura K;Mitani K;Kaneda H.;Takeda K.;Ota T.;Kaduka Y.;Smyth M.J.;杉浦大輔;中山勝文;野見武男;野見武男;中山勝文;竹田和由;山戸一郎;八木田秀雄;Kijima Mika
• 通讯作者: Kijima Mika

Jagged2 is cruicial for exerting killer activity of NK cells

Jagged2对于发挥NK细胞的杀伤活性至关重要

• 作者: Mika;Kijima;et. al.
• 通讯作者: et. al.

Dendritic cell-mediated NK cell activation is controlled by Jagged2-Notch interaction

• DOI: 10.1073/pnas.0709919105
• 发表时间: 2008-05-13
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Kijima, Mika;Yamaguchi, Takeshi;Yasutomo, Koji
• 通讯作者: Yasutomo, Koji