CD8 coreceptor extinction in signaled CD4+ CD8+ thymocytes:: Coordinate roles for both transcriptional and posttranscriptional regulatory mechanisms in developing thymocytes
CD8 coreceptor extinction in signaled CD4+ CD8+ thymocytes:: Coordinate roles for both transcriptional and posttranscriptional regulatory mechanisms in developing thymocytes
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DOI：
10.1128/mcb.20.11.3852-3859.2000
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发表时间：
2000-06-01
影响因子：
5.3
通讯作者：
Singer, A
中科院分区：
文献类型：
--
作者：
Cibotti, R;Bhandoola, A;Singer, A
胸腺中T细胞发育的特征在于CD 4和CD 8辅助受体分子表达模式的改变以及CD 4和CD 8基因转录的改变。在对T细胞受体（TCR）信号的反应中，胸腺细胞通过发育转变，如CD 4（+）CD 8（+）（双阳性[DP]）胸腺细胞转化为中间型CD 4（+）CD 8（-）胸腺细胞，这似乎需要比单独转录调控更快的辅受体表达变化。因此，我们认为TCR刺激DP胸腺细胞不仅影响辅助受体基因转录，而且影响辅助受体RNA稳定性的可能性。事实上，我们发现DP胸腺细胞中的TCR信号迅速使预先存在的CD 4和CD 8辅助受体RNA不稳定，导致其快速消除。对于CD 8 α，辅助受体RNA的不稳定性取决于RNA非编码区中的靶序列。TCR信号也差异影响DP胸腺细胞的辅助受体基因转录，终止CD 8 α基因转录，但仅短暂降低CD 4基因转录。因此，转录后和转录调节机制协调作用，在信号DP胸腺细胞，以促进这些细胞迅速转化为中间的CD 4 + CD 8-胸腺细胞。我们认为，预先存在的辅助受体RNA的不稳定是一种机制，通过这种机制，辅助受体表达在发育中的胸腺细胞在这些细胞分化的关键点迅速改变。
T-cell development in the thymus is characterized by changing expression patterns of CD4 and CD8 coreceptor molecules and by changes in CD4 and CD8 gene transcription. In response to T-cell receptor (TCR) signals, thymocytes progress through developmental transitions, such as conversion of CD4(+)CD8(+) (double-positive [DP]) thymocytes into intermediate CD4(+)CD8(-) thymocytes, that appear to require more-rapid changes in coreceptor expression than can be accomplished by transcriptional regulation alone. Consequently, we considered the possibility that TCR stimulation of DP thymocytes not only affects coreceptor gene transcription but also affects coreceptor RNA stability. Indeed, we found that TCR signals in DP thymocytes rapidly destabilized preexisting CD4 and CD8 coreceptor RNAs, resulting in their rapid elimination. Destabilization of coreceptor RNA was shown for CD8 alpha to be dependent on target sequences in the noncoding region of the RNA. TCR signals also differentially affected coreceptor gene transcription in DP thymocytes, terminating CD8 alpha gene transcription but only transiently reducing CD4 gene transcription. Thus, posttranscriptional and transcriptional regulatory mechanisms act coordinately in signaled DP thymocytes to promote the rapid conversion of these cells into intermediate CD4+CD8- thymocytes. We suggest that destabilization of preexisting coreceptor RNAs is a mechanism by which coreceptor expression in developing thymocytes is rapidly altered at critical points in the differentiation of these cells.