A role for E2F1 in the induction of apoptosis during thymic negative selection.
A role for E2F1 in the induction of apoptosis during thymic negative selection.
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发表时间：
2000-02
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通讯作者：
I. García;M. Murga;A. Vicario;S. Field;A. Zubiaga
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作者：
I. García;M. Murga;A. Vicario;S. Field;A. Zubiaga
胸腺负选择是表达识别自身的 T 细胞受体的成熟胸腺细胞被凋亡细胞死亡消除的过程。人们对这种现象发生的分子机制知之甚少。值得注意的是，参与细胞死亡甚至胸腺细胞死亡的基因，如 Fas、Fas-配体、p53、caspase-1、caspase-3、caspase-9 和 Bcl-2 已被发现不是正常胸腺阴性选择所必需的。我们之前已经证明E2F1缺陷小鼠的胸腺细胞凋亡存在缺陷。在这里，我们表明 E2F1 是正常胸腺负选择所必需的。此外，我们在胸腺克隆缺失过程中观察到E2F1依赖性p53蛋白水平增加，这表明E2F1通过p53依赖性机制调节激活诱导的自身反应性胸腺细胞凋亡。相比之下，其他作用于发育中胸腺细胞的凋亡途径，例如糖皮质激素诱导的细胞死亡，并不是由 E2F1 介导的。逃避胸腺阴性选择的T淋巴细胞迁移到外周免疫系统，但似乎不具有自身反应性，这表明可能存在不依赖于E2F1的外周耐受机制，从而保护小鼠免于发生自身免疫反应。我们期望 E2F1 缺陷小鼠将为理解胸腺负选择的分子机制和免疫学重要性提供有用的工具。
Thymic negative selection is the process in which maturing thymocytes that express T-cell receptors recognizing self are eliminated by apoptotic cell death. The molecular mechanism by which this occurs is poorly understood. Notably, genes involved in cell death, even thymocyte death, such as Fas, Fas-ligand, p53, caspase-1, caspase-3, and caspase-9, and Bcl-2 have been found to not be required for normal thymic negative selection. We have demonstrated previously that E2F1-deficient mice have a defect in thymocyte apoptosis. Here we show that E2F1 is required for normal thymic negative selection. Furthermore, we observed an E2F1-dependent increase of p53 protein levels during the process of thymic clonal deletion, which suggests that E2F1 regulates activation-induced apoptosis of self-reactive thymocytes by a p53-dependent mechanism. In contrast, other apoptotic pathways operating on developing thymocytes, such as glucocorticoid-induced cell death, are not mediated by E2F1. The T lymphocytes that escape thymic negative selection migrate to the peripheral immune system but do not appear to be autoreactive, indicating that there may exist E2F1-independent mechanisms of peripheral tolerance, which protect mice from developing an autoimmune response. We expect that E2F1-deficient mice will provide a useful tool for understanding the molecular mechanism of and the immunological importance of thymic negative selection.