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

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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