Molecular mechanism of selective development in thymocytes analysing DP specific molcules

胸腺细胞选择性发育的分子机制分析DP特异性分子

• 批准号: 09470098
• 负责人: HABU Sonoko
• 金额: $ 4.16万
• 依托单位: Tokai University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09470098/
• 关键词: T cell receptor; positive selection; proliferative inhibition; gene rearrangement; MAPK; thymocyte; TCR; シスエレメント; germ line転写

In the intrathymic development, only DP cells which are rescued from the cell death by TCR mediated selecting development into SP cells. At the same time, it is strongly suggested that apoptosis of DP cells is inhibited when TCR mediated signaling suppresses further rearrangement of TCR-alpha gene. In this study, we investigated the molecular mechanism of cell survival /proliferating suppression on DP cells receiving positive selection, and obtained the following results. 1) CD45 is involved in proloferating suppression of DP cells. 2) DP cells easily die when DP cells receive TCR mediated signaling at the proliferating stage. 3) JNK, one of MAPK family, functions for the positive selection by blocking the cell death of DP cells, which was provident when DP cells is integrated with dominant negative gene of Seki, a JNK kinase, showed apoptosis. 4) As a novel cis- element with a stage specificity, the upstream region of Jalpha49 segment was shown to regulated the gene rearrangement and germ line transcription of Jct49-45. This indicates that TCR-alpha gene rearrangement requires a stage specific cis-element as well as alpha enhancer.

在胸腺内发育中，只有通过TCR介导的细胞死亡而被拯救的DP细胞才会选择发育成SP细胞。同时，强烈表明当TCR介导的信号传导抑制TCR-α基因的进一步重排时，DP细胞的凋亡受到抑制。在本研究中，我们研究了接受正选择的DP细胞存活/增殖抑制的分子机制，并获得了以下结果。 1) CD45参与DP细胞的增殖抑制。 2）当DP细胞在增殖阶段接受TCR介导的信号传导时，DP细胞很容易死亡。 3) JNK是MAPK家族的一员，通过阻断DP细胞的死亡来发挥正向选择的作用，当DP细胞与JNK激酶Seki的显性失活基因整合时，显示细胞凋亡。 4）作为一种具有阶段特异性的新型顺式元件，Jalpha49片段的上游区域被证明能够调节Jct49-45的基因重排和种系转录。这表明TCR-α基因重排需要阶段特异性顺式元件以及α增强子。

项目成果

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Takehito Sato：“CD45 可以充当从早期 CD4^ CD8^ 胸腺细胞向晚期 CD4^ CD8^ 胸腺细胞转变的阴性调节因子。”

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