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首页 » J.Immunology:转录调控因子Dec2在Th2细胞分化中的调控机制

J.Immunology:转录调控因子Dec2在Th2细胞分化中的调控机制

来源:中科院 2009-11-12 10:37

10月30日,免疫学专业期刊《免疫学杂志》(Journal of Immunology)发表了中国科学院上海生命科学研究院生物化学与细胞生物学研究所孙兵研究组最新研究成果:转录调控因子Dec2在Th2细胞分化中的调控机制。这一研究成果进一步揭示了Th2细胞分化的调控网络,并有助于了解Th2细胞介导的过敏性疾病的发病机制。

过敏性疾病如过敏性哮喘主要由Th2细胞所介导。当机体幼稚Th细胞被抗原递呈细胞激活后,经过克隆增殖与细胞分化,形成不同的细胞亚型如Th1,Th2,Th17和Treg等。不同的细胞亚型介导不同的疾病,其中Th2细胞分泌大量的白介素4,5和13,在抗寄生虫以及过敏反应中起到重要的作用。然而Th2细胞分化的精确调控仍不清楚,深入研究Th2细胞分化的调控网络,对包括哮喘在内的过敏性疾病的治疗和预防有重要意义。

孙兵研究组的刘智多和李振虎博士发现,一个从属于bHLH (basic helix-loop-helix) 超家族的转录因子Dec2, 在Th细胞朝向Th2方向分化的过程中被逐渐地诱导表达,而且这一趋势在Th2细胞分化的后期显得尤为明显。在Th2细胞诱导的条件下,即在IL-4信号开放的条件下,Dec2能够强力促进Th2细胞的分化。相反,如果用RNA干扰的方法下调细胞内的Dec2的表达水平,Th2细胞分化的进程就会受到抑制。另外,他们在用OVA诱导的小鼠过敏性哮喘模型中发现,相比于对照小鼠Dec2转基因小鼠里检测到了更强的Th2免疫反应。此项工作揭示Dec2是通过上调IL-2R的α亚基,也就是CD25的表达水平,来增强IL-2信号通路,进而更好地促进Th2的分化。该研究不仅发现了一个新的Th2细胞分化调控机制,阐明了IL-2和IL-4在Th2的分化中发挥了同等的作用,还为过敏性疾病的治疗提供了一个新的药物靶点。

此项研究成果得到科技部973、国家自然科学基金、上海市科学技术委员会和中国科学院的资金资助。浙江大学项春生教授在用DNA芯片技术筛选Dec2基因的研究中,做出了重要贡献。(生物谷Bioon.com)

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The Journal of Immunology, 2009, 183, 6320 -6329 doi:10.4049/jimmunol.0900975

Dec2 Promotes Th2 Cell Differentiation by Enhancing IL-2R Signaling1

Zhiduo Liu,2* Zhenhu Li,2* Kairui Mao,* Jia Zou,* Yuan Wang,* Zhiyun Tao,* Guomei Lin,* Lin Tian,* Yongyong Ji,* Xiaodong Wu,* Xueliang Zhu,* Shuhui Sun, Weiguang Chen, Charlie Xiang,3 and Bing Sun3*

*Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai, China;  Institute Pasteur of Shanghai, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai, China;  Fudan University School of Medicine, Shanghai, China; and  State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China

Th cell differentiation is precisely regulated by thousands of genes at different stages. In the present study, we demonstrate that Dec2, a transcription factor belonging to the bHLH (basic helix-loop-helix) superfamily, is progressively induced during the course of Th2 differentiation, especially at the late stage. The up-regulated Dec2 can strongly promote Th2 development under Th2-inducing conditions, as evidenced by retrovirus-mediated gene transfer or transgenic manipulation. In addition, an enhancement of Th2 responses is also detectable in Dec2 transgenic mice in vivo. Conversely, RNA interference-mediated suppression of endogenous Dec2 could attenuate Th2 differentiation. Finally, we show that the enhanced Th2 development is at least in part due to substantial up-regulation of CD25 expression elicited by Dec2, thereby resulting in hyperresponsiveness to IL-2 stimulation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported by Grants from the National Natural Science Foundation of China (30530700, 30623003, 30600568, 30721065, 90713044, 30600308, 30801011, 30870126) and the CAS project (KSCX1-YW-R-43), a grant from the SIBS project (2007KIP301), grants from the Ministry of Science and Technology (2006CB504300, 2007CB512404, 2006AA02A247, 20072714), grants from the Technology Commission of Shanghai Municipality (88014199, 07DZ22916, 07XD14033, 064319034, 08431903004, 2008ZX10206, 08DZ2291703), the EU project (FP6-2005-SSP-5-B, SP5B-CT-2006-044161), the National Basic Research Program of China (973 Program, No. 2007CB513001) and a grant from the E-institutes of Shanghai Universities Immunology Division.
2 Z. Liu and Z. Li contributed equally to this study.
3 Address correspondence and reprint requests to Dr. Bing Sun, Laboratory of Molecular Immunology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, China or Dr. Charlie Xiang, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
4 Abbreviations used in this paper: bHLH, basic helix-loop-helix; hCD4, human CD4; Treg, regulatory T cell; siRNA, short-interfering RNA; MFI, mean fluorescence intensity; RNAi, RNA interference; iTreg, induced regulatory T cell; MSCV, mouse stem cell virus.
5 The online version of this article contains supplementary material.

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