調(diào)節(jié)性T細(xì)胞（Treg）在限制自身免疫和慢性炎癥中發(fā)揮著重要作用,， 而調(diào)節(jié)性T細(xì)胞的生成由轉(zhuǎn)錄因子Foxp3調(diào)控,。
5月10日，國際著名期刊Immunity 在線發(fā)表了圣猶大兒童研究醫(yī)院等機構(gòu)的一篇題為Loss of Epigenetic Modification Driven by the Foxp3 Transcription Factor Leads to Regulatory T Cell Insufficiency的研究論文,，研究發(fā)現(xiàn)Foxp3驅(qū)動的表觀遺傳修飾失控將導(dǎo)致調(diào)節(jié)性T細(xì)胞的不足,，進(jìn)而使得機體在易感環(huán)境下發(fā)生自身免疫。
Foxp3gfp 是一個亞等位基因,。研究發(fā)現(xiàn),，它在NOD背景的小鼠中大大加速自身免疫糖尿病的發(fā)生。雖然在NOD和C57B L/6背景的小鼠中,，天然調(diào)節(jié)性T細(xì)胞的生長和功能在體外沒有顯著地改變,，但是在炎癥環(huán)境下天然調(diào)節(jié)性T細(xì)胞功能被擾亂，并且TGF-β介導(dǎo)的調(diào)節(jié)性T細(xì)胞的生長也在減緩,。Foxp3gfp不能與組氨酸乙酰轉(zhuǎn)移酶Tip60,、組氨酸脫乙酰酶HDAC7和Ikaros家族鋅指4(Eos)等發(fā)生相互作用，這將減少Foxp3的乙?；?，并提高K48J連接的多聚泛素化。這些將導(dǎo)致Foxp3驅(qū)動的轉(zhuǎn)錄譜改變和Foxp3介導(dǎo)的基因表達(dá)水平的降低,。
這表明,，F(xiàn)oxp3驅(qū)動的表觀遺傳修飾失控將導(dǎo)致調(diào)節(jié)性T細(xì)胞的不足，進(jìn)而使得機體在易感環(huán)境下會發(fā)生自身免疫,。(生物谷Bioon.com)
doi.org/10.1016/j.immuni.2012.03.020
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PMID:
Loss of Epigenetic Modification Driven by the Foxp3 Transcription Factor Leads to Regulatory T Cell Insufficiency
Matthew L.Bettini,Fan Pan,Maria Bettini,David Finkelstein,Jerold E.Rehg,Stefan Floess,Bryan D.Bell,Steven F.Ziegler,Jochen Huehn,Drew M.Pardoll,Dario A.A.Vignali
1 Department of Immunology,， St. Jude Children's Research Hospital， Memphis,， TN 38105,USA
2 Bioinformatics,， St. Jude Children's Research Hospital， Memphis,， TN 38105,， USA
3 Department of Pathology， St. Jude Children's Research Hospital,， Memphis,， TN 38105,USA
4 Immunology and Hematopoiesis Division， Sidney Kimmel Comprehensive Cancer Center,， Johns Hopkins University School of Medicine,， Baltimore， MD 21231,， USA
5 Experimental Immunology,， Helmholtz Centre for Infection Research,， Inhoffenstr. 7， 38124 Braunschweig,Germany
6 Benaroya Research Institute,， Seattle,， WA 98101， USA
Summary
Regulatory T (Treg) cells,driven by the Foxp3 transcription factor,are responsible for limiting autoimmunity and chronic inflammation. We showed that a well-characterized Foxp3gfp reporter mouse,which expresses an N-terminal GFP-Foxp3 fusion protein,is a hypomorph that causes profoundly accelerated autoimmune diabetes on a NOD background. Although natural Treg cell development and in vitro function are not markedly altered in Foxp3gfp NOD and C57BL/6 mice,Treg cell function in inflammatory environments was perturbed and TGF-β-induced Treg cell development was reduced. Foxp3gfp was unable to interact with the histone acetyltransferase Tip60,the histone deacetylase HDAC7,and the Ikaros family zinc finger 4,， Eos,which led to reduced Foxp3 acetylation and enhanced K48-linked polyubiquitylation. Collectively this results in an altered transcriptional landscape and reduced Foxp3-mediated gene repression,notably at the hallmark IL-2 promoter. Loss of controlled Foxp3-driven epigenetic modification leads to Treg cell insufficiency that enables autoimmunity in susceptible environments.
