Retinoblastoma 1 protects T cell maturation from premature apoptosis by inhibiting E2F1
Retinoblastoma 1 protects T cell maturation from premature apoptosis by inhibiting E2F1
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视网膜母细胞瘤 1 通过抑制 E2F1 保护 T 细胞成熟免于过早凋亡
DOI：
10.1242/dev.158139
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发表时间：
2018-01-01
期刊：
影响因子：
4.6
通讯作者：
Zhang, Yiyue
中科院分区：
文献类型：
--
作者：
Zhang, Zili;Liu, Wei;Zhang, Yiyue
T淋巴细胞是获得性免疫系统的关键细胞成分，在细胞介导的免疫中发挥着至关重要的作用。T细胞的发育发生在胸腺，其中95%的未成熟胸腺细胞会通过细胞凋亡被清除。已知视网膜母细胞瘤1（Rb1）的靶基因之一Zeb1发生突变，会导致小鼠体内未成熟T细胞数量减少。E2F1是一种与RB1相互作用的蛋白质，已被证明可通过干扰胸腺细胞凋亡来调节成熟T细胞的发育。然而，Rb1是否在体内调节胸腺细胞发育仍有待进一步研究。在此，我们利用斑马鱼模型来探究Rb1在T细胞发育中的作用。我们发现，Rb1缺陷型斑马鱼在早期发育过程中T细胞数量显著减少，这归因于未成熟T细胞以半胱天冬酶（caspase）依赖的方式加速凋亡。我们进一步表明，E2F1过表达可模拟Rb1突变体中T淋巴细胞减少的表型，而E2F1基因敲低则可挽救Rb1缺陷型突变体的这一表型。总体而言，我们的数据表明，Rb1 - E2F1 - 半胱天冬酶轴对于在T淋巴细胞早期成熟过程中保护未成熟T细胞免于凋亡至关重要。
T lymphocytes are key cellular components of an acquired immune system and play essential roles in cell-mediated immunity. T cell development occurs in the thymus where 95% of immature thymocytes are eliminated via apoptosis. It is known that mutation of Zeb1, one of the retinoblastoma 1 (Rb1) target genes, results in a decrease in the number of immature T cells in mice. E2F1, an RB1-interacting protein, has been shown to regulate mature T cell development by interfering with thymocyte apoptosis. However, whether Rb1 regulates thymocyte development in vivo still needs to be further investigated. Here, we use a zebrafish model to investigate the role of Rb1 in T cell development. We show that Rb1- deficient fish exhibit a significant reduction in T cell number during early development that it is attributed to the accelerated apoptosis of immature T cells in a caspase-dependent manner. We further show that E2F1 overexpression could mimic the reduced T lymphocytes phenotype of Rb1 mutants, and E2F1 knockdown could rescue the phenotype in Rb1- deficient mutants. Collectively, our data indicate that the Rb1- E2F1-caspase axis is crucial for protecting immature T cells from apoptosis during early T lymphocyte maturation.