国际学术期刊《The Journal of Immunology》近日发表了中科院上海生科院生化与细胞所刘小龙研究组关于T淋巴细胞定向分化调控机制的最新成果“Epigenetic Silencing of Cd8 Genes by ThPOK-Mediated Deacetylation during CD4 T Cell Differentiation”。
T细胞定向分化过程中，伴随着CD4和CD8共受体分子相互排斥表达模式的逐步建立，具有辅助性功能的CD4 T淋巴细胞和具杀伤性功能的CD8 T淋巴细胞最终得以分化成熟并迁移到外周行使免疫功能。CD4和CD8受体分子在这个过程中相互排斥的表达模式是如何形成的一直是过去相当长的一段时间内基础免疫学研究的重点。其中，CD4分子的调控机制研究得比较深入，发现CD8 T淋巴细胞定向分化过程中Cd4沉默子和转录因子RUNX3介导了Cd4基因的转录抑制；而在CD4 T淋巴细胞定向分化过程中CD8分子是如何被沉默的并不清楚。博士生芮金秀等的研究工作揭示转录因子ThPOK在这个过程中发挥了关键作用。
首先，ThPOK能直接结合包括5个增强子和1个启动子的Cd8基因的顺式调控元件。通过招募去乙酰化酶，ThPOK介导了Cd8基因内组蛋白的去乙酰化作用，进而将Cd8基因推进了异染色区域，导致其转录受到稳定的抑制，蛋白表达逐渐被沉默。在ThPOK转基因小鼠，Cd8 基因的转录和表达受到的抑制被提早到双阳性的早期前体（DP 胸腺细胞）阶段。相反，在ThPOK缺失的小鼠中，Cd8基因的转录和表达明显增强，CD4 T淋巴细胞定向分化被阻滞。该研究不仅为转录因子ThPOK 鉴定到作用靶点；还阐明了CD4 T淋巴细胞定向分化过程中CD8 分子沉默的调控机制。为此，《The Journal of Immunology》在“In This Issue”板块将他们的工作作为“研究亮点”进行了点评。
该项研究获得了国家科技部、国家自然科学基金委和上海市的经费支持。（生物谷Bioon.com）
doi:10.4049/jimmunol.1201077
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Epigenetic Silencing of Cd8 Genes by ThPOK-Mediated Deacetylation during CD4 T Cell Differentiation
Jinxiu Rui, Haifeng Liu, Xiaoyan Zhu, Yu Cui and Xiaolong Liu
Intrathymic CD4/CD8 differentiation is a process that establishes the mutually exclusive expression profiles of the CD4 and CD8 T cell lineage. The RUNX3-mediated silencing of CD4 in CD8 lineage cells has been well documented; however, it is unclear how CD8 is silenced during CD4 lineage differentiation. In this study, we report that, by directly binding the CD8 locus, ThPOK works as a negative regulator that mediates the deacetylation of Cd8 genes and repositions the CD8 alleles close to heterochromatin during the development of the CD4 lineage. The ectopic expression of ThPOK resulted in increased recruitment of histone deacetylases at Cd8 loci; the enhanced deacetylation of Cd8 genes eventually led to impaired Cd8 transcription. In the absence of ThPOK, the enhanced acetylation and transcription of Cd8 genes were observed. The results of these studies showed that Cd8 loci are the direct targets of ThPOK, and, more importantly, they provide new insights into CD8 silencing during CD4 lineage commitment.
