10月27日，欧洲免疫学杂志(European Journal of Immunology)在线发表了中科院上海生科院生化与细胞所刘小龙研究组的研究论文“Interferon regulatory factor 4 regulates thymocyte differentiation by repressing Runx3 expression”。
胸腺细胞在胸腺中定向分化为CD4 和CD8 两个T细胞类群，在建立免疫功能的同时，获得自身免疫耐受性。然而，调控CD4/CD8细胞分化定向的分子机制仍然知之甚少。干扰素调节因子4（IRF4）一直被认为只在成熟的淋巴细胞中表达，维持着CD4 T细胞的功能、分化及自稳平衡；而其在胸腺细胞分化成熟过程中的作用尚未涉及。
刘小龙研究组研究发现，在胸腺细胞分化成熟过程中，IRF4的表达受TCR信号调控；并且在CD4 SP 和CD8 SP细胞中差异表达。转基因小鼠模型实验表明，T细胞特异性过表达IRF4促进CD4定向并抑制CD8定向；他们的研究还表明，IRF4招募组蛋白去乙酰化酶HDAC1，通过直接结合到CD8细胞分化决定因子Runx3的基因的远端启动子上，使其组蛋白去乙酰化，从而抑制Runx3的表达。他们的研究结果揭示了IRF4调控胸腺细胞分化成熟的机制：持续的TCR信号促进IRF4的表达，IRF4通过抑制Runx3的转录，抑制CD8定向相关分子的表达，促进胸腺细胞定向分化为CD4 T细胞。该研究还将胸腺细胞的定向分化与免疫功能关联起来。
该研究工作得到国家自然科学基金委，中国科学院和科技部重大科学研究计划的经费资助。（生物谷Bioon.com）
生物谷推荐英文摘要：
European Journal of Immunology DOI: 10.1002/eji.201040570
Interferon regulatory factor 4 regulates thymocyte differentiation by repressing Runx3 expression
Yonghao Cao1,?, Hai Li1,?, Yang Sun1, Xufeng Chen1, Haifeng Liu1, Xiang Gao2, Xiaolong Liu1,*
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.
