调节性T细胞（Treg）在限制自身免疫和慢性炎症中发挥着重要作用， 而调节性T细胞的生成由转录因子Foxp3调控。
5月10日，国际著名期刊Immunity 在线发表了圣犹大儿童研究医院等机构的一篇题为Loss of Epigenetic Modification Driven by the Foxp3 Transcription Factor Leads to Regulatory T Cell Insufficiency的研究论文，研究发现Foxp3驱动的表观遗传修饰失控将导致调节性T细胞的不足，进而使得机体在易感环境下发生自身免疫。
Foxp3gfp 是一个亚等位基因。研究发现，它在NOD背景的小鼠中大大加速自身免疫糖尿病的发生。虽然在NOD和C57B L/6背景的小鼠中，天然调节性T细胞的生长和功能在体外没有显著地改变，但是在炎症环境下天然调节性T细胞功能被扰乱，并且TGF-β介导的调节性T细胞的生长也在减缓。Foxp3gfp不能与组氨酸乙酰转移酶Tip60、组氨酸脱乙酰酶HDAC7和Ikaros家族锌指4(Eos)等发生相互作用，这将减少Foxp3的乙酰化，并提高K48J连接的多聚泛素化。这些将导致Foxp3驱动的转录谱改变和Foxp3介导的基因表达水平的降低。
这表明，Foxp3驱动的表观遗传修饰失控将导致调节性T细胞的不足，进而使得机体在易感环境下会发生自身免疫。(生物谷Bioon.com)
doi.org/10.1016/j.immuni.2012.03.020
PMC:
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.
