Interferon regulatory factor 4 regulates thymocyte differentiation by repressing Runx3 expression
Interferon regulatory factor 4 regulates thymocyte differentiation by repressing Runx3 expression
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干扰素调节因子 4 通过抑制 Runx3 表达调节胸腺细胞分化
DOI：
10.1002/eji.201040570
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发表时间：
2010-11-01
影响因子：
5.4
通讯作者：
Liu, Xiaolong
中科院分区：
文献类型：
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作者：
Cao, Yonghao;Li, Hai;Liu, Xiaolong
转录因子干扰素调节因子4(IRF4)最初被发现在淋巴细胞中优先表达，对成熟T和B淋巴细胞的功能、分化和动态平衡都是必需的。最近的研究表明，IRF4也参与了B细胞的早期发育。然而，IRF4在胸腺内T细胞发育中的作用仍不清楚。在这项研究中，我们发现IRF4在TCR信号的胸腺细胞中上调，并且主要在CD4单阳性(SP)细胞中表达，而在CD8SP细胞中不表达。T细胞特异性过表达IRF4可抑制CD8SP胸腺细胞的生成和成熟。进一步的分析表明，IRF4选择性地结合到Runx3的远端启动子区域并抑制其转录，这可能是通过中间的CD4+CD8low细胞和CD4SP胸腺细胞中组蛋白H3和H4的去乙酰化来实现的。与Runx3缺乏症类似，转基因表达IRF4不仅导致中间细胞CD8低表达细胞和CD8 SP细胞表面分子异常高表达，而且使CD8+T细胞功能受损。综上所述，我们的研究结果表明，IRF4在调节Runx3的表达和调节CD4+/CD8+胸腺细胞分化中起重要作用。
The transcription factor interferon regulatory factor 4 (IRF4) was originally found to be preferentially expressed in lymphoid cells and to be required for the function, differentiation, and homeostasis of both mature T and B lymphocytes. Recent studies have indicated that IRF4 is also involved in early B‐cell development. However, the role of IRF4 in intrathymic T‐cell development remains unknown. In this study, we show that IRF4 is upregulated in TCR‐signaled thymocytes and is predominantly expressed in CD4 single‐positive (SP), but not in CD8 SP, cells. T‐cell‐specific overexpression of IRF4 impaired the generation and maturation of CD8 SP thymocytes. Further analysis revealed that IRF4 selectively bound to the distal promoter region of Runx3 and repressed its transcription, probably through the deacetylation of histones H3 and H4 in intermediate CD4+CD8low cells and CD4 SP thymocytes. Similar to the effect of Runx3 deficiency, transgenic expression of IRF4 led not only to an aberrantly high expression of CD4 surface molecules on intermediate CD4+CD8low cells and CD8 SP thymocytes, but also impaired CD8+ T‐cell function. Taken together, our data suggest that IRF4 plays an important role in the regulation of Runx3 expression and CD4+/CD8+ thymocyte differentiation.