Egr2 is required for Bcl-2 induction during positive selection.
Egr2 is required for Bcl-2 induction during positive selection.
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DOI：
10.4049/jimmunol.181.11.7778
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发表时间：
2008-12-01
期刊：
影响因子：
--
通讯作者：
Wiest DL
中科院分区：
文献类型：
--
作者：
Lauritsen JP;Kurella S;Lee SY;Lefebvre JM;Rhodes M;Alberola-Ila J;Wiest DL
T细胞受体（TCR）特异性库是由胸腺中的一个选择过程建立的，在这个过程中，前体的存活和成熟是由TCR信号的性质决定的。决定前体是存活、成熟还是被诱导死亡的信号差异仍然知之甚少。在参与执行由tcr -配体相互作用启动的分化过程的分子效应物中，有一个被称为早期生长反应基因（Egr）的锌指转录因子家族。事实上，Egr1基因的消融会损害配体诱导的成熟（正选择），但不会损害配体诱导的缺失（负选择）。egr1缺失导致的阳性选择的部分损伤不会因同时缺失另一个Egr家族成员Egr3而增强。因此，我们询问这是否来自另一个家庭成员Egr2的补偿。在这篇论文中，我们证明了Egr2的缺失会损害CD4和CD8 SP胸腺细胞的阳性选择。有趣的是，许多参与阳性选择和T细胞分化的基因在缺乏egr2的胸腺细胞中正常上调。然而，在正向选择的后期，Bcl-2的上调并不持续。这一缺陷至少在一定程度上是Egr2缺陷胸腺细胞发育受阻的原因，因为Bcl-2的强制表达可以挽救Egr2−/−胸腺细胞中的T细胞发育。综上所述，这些数据表明，在阳性选择过程中，Egr2在生存分子Bcl-2的上调中起着核心作用。
The repertoire of T cell receptor (TCR) specificities is established by a selection process in the thymus during which precursor survival and maturation is dictated by the nature of the TCR signals. The differences in signals that determine whether precursors will survive and mature or be induced to die remain poorly understood. Among the molecular effectors involved in executing the differentiation process initiated by TCR-ligand interactions is a family of Zn-finger transcription factors termed early growth response genes (Egr). Indeed, ablation of the Egr1 gene impairs ligand-induced maturation (positive selection) but not ligand-induced deletion (negative selection). The partial impairment of positive selection by Egr1-deficiency is not enhanced by simultaneous deletion of another Egr family member, Egr3. Accordingly, we asked whether this results from compensation by another family member, Egr2. In this manuscript, we demonstrate that deletion of Egr2 impairs positive selection of both CD4 and CD8 SP thymocytes. Interestingly, many of the genes involved in positive selection and T cell differentiation are upregulated normally in the Egr2-deficient thymocytes. However, Bcl-2 upregulation is not sustained during late stages of positive selection. This defect is at least partially responsible for the developmental blockade in Egr2-deficient thymocytes, as enforced expression of Bcl-2 rescues T cell development in Egr2−/− thymocytes. Taken together, these data suggest that Egr2 plays a central role in the upregulation of the survival molecule Bcl-2 during positive selection.
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