来自清华大学和美国斯隆凯特琳癌症中心的科学家日前揭示了Foxo1在“依赖于Treg细胞、独立于Foxo3”的免疫耐受性的控制中所起的一个关键作用。作者提出,Treg细胞指派从演化上来说古老的Akt-Foxo1信号通道来控制对Treg细胞功能来说必不可少的一个新颖基因程序。

-2012年11月22日《自然》

中文翻译


【题目】新的Foxo1依赖的转录程序控制Treg细胞功能

【译文】调节性T (Treg)细胞的特征是表达头叉转录因子盒P3(FOXP3),它通过抑制自身破坏性免疫响应,来维持免疫稳态。Foxp3作为后起作用的分化因子控制Treg细胞稳态和功能,而早期Treg细胞系定型受到Akt激酶和头叉盒O(Foxo)转录因子家族的调控。然而,Foxo蛋白是否可以超越Treg细胞定型阶段以控制Treg细胞稳态和功能还不清楚。 本研究表明Foxo1是Treg细胞功能的关键调控因子。Treg细胞表达大量的Foxo1并表现出T细胞受体诱导的Akt活化、Foxo1磷酸化及Foxo1核清除的减弱。Foxo1 Treg细胞特异性缺失的小鼠产生了一种致命的炎症疾病,严重性类似于在Foxp3缺乏的小鼠中观察到那样,但并无Treg细胞的损失。对Foxo1结合位点的全基因组分析揭示了约300个Foxo1结合靶基因,包括促炎细胞因子Ifng,这些靶基因并不直接受到Foxp3的调控。这些发现表明进化古老的Akt–Foxo1信号通路控制一种对于Treg细胞功能必不可少的新的遗传程序。

英文原稿


[Title]: Novel Foxo1-dependent transcriptional programs control Treg cell function

[Authors]:Weiming Ouyang,1 Will Liao,2, 3 Chong T. Luo,1, 4 Na Yin,1 Morgan Huse,1 Myoungjoo V. Kim,1 Min Peng,1 Pamela Chan,1 Qian Ma,1 Yifan Mo,2, 3 Dies Meijer,5 Keji Zhao,6 Alexander Y. Rudensky,1, 7 Gurinder Atwal,2 Michael Q. Zhang8, 9 & Ming O. Li1  

[Abstract]Regulatory T (Treg) cells, characterized by expression of the transcription factor forkhead box P3 (Foxp3), maintain immune homeostasis by suppressing self-destructive immune responses. Foxp3 operates as a late-acting differentiation factor controlling Treg cell homeostasis and function, whereas the early Treg-cell-lineage commitment is regulated by the Akt kinase and the forkhead box O (Foxo) family of transcription factors. However, whether Foxo proteins act beyond the Treg-cell-commitment stage to control Treg cell homeostasis and function remains largely unexplored. Here we show that Foxo1 is a pivotal regulator of Treg cell function. Treg cells express high amounts of Foxo1 and display reduced T-cell-receptor-induced Akt activation, Foxo1 phosphorylation and Foxo1 nuclear exclusion. Mice with Treg-cell-specific deletion of Foxo1 develop a fatal inflammatory disorder similar in severity to that seen in Foxp3-deficient mice, but without the loss of Treg cells. Genome-wide analysis of Foxo1 binding sites reveals ~300 Foxo1-bound target genes, including the pro-inflammatory cytokine Ifng, that do not seem to be directly regulated by Foxp3. These findings show that the evolutionarily ancient Akt–Foxo1 signalling module controls a novel genetic program indispensable for Treg cell function.

原文地址

http://www.nature.com/nature/journal/v491/n7425/full/nature11581.html

 

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