Molecular mechanism of selective development in thymocytes analysing DP specific molcules

在胸腺内发育过程中，只有TCR从细胞死亡中挽救出来的DP细胞才有选择性发育为SP细胞。同时，TCR介导的信号转导抑制了TCR-α基因的进一步重排，从而抑制了DP细胞的凋亡。在本研究中，我们对接受阳性选择的DP细胞的细胞存活/增殖抑制的分子机制进行了研究，并获得了以下结果。1)CD45参与了对DP细胞的增殖抑制。2)当DP细胞在增殖期接受TCR介导的信号时，DP细胞容易死亡。3)JNK是MAPK家族中的一员，它通过阻断DP细胞的死亡而发挥正向选择的作用，当DP细胞与显性负向基因Seki整合后，JNK激酶呈凋亡状态。4)Jalpha49基因上游区域作为一个新的具有阶段特异性的顺式元件，调控着Jct49-45的基因重排和生殖系转录。这表明TCR-α基因重排需要一个阶段特异的顺式元件和α增强子。

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.