Loss of epigenetic modification driven by the Foxp3 transcription factor leads to regulatory T cell insufficiency.
Loss of epigenetic modification driven by the Foxp3 transcription factor leads to regulatory T cell insufficiency.
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DOI：
10.1016/j.immuni.2012.03.020
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发表时间：
2012-05-25
期刊：
影响因子：
32.4
通讯作者：
Vignali DA
中科院分区：
文献类型：
--
作者：
Bettini ML;Pan F;Bettini M;Finkelstein D;Rehg JE;Floess S;Bell BD;Ziegler SF;Huehn J;Pardoll DM;Vignali DA
由 Foxp3 转录因子驱动的调节性 T (Treg) 细胞负责限制自身免疫和慢性炎症。我们发现，表达 N 端 GFP-Foxp3 融合蛋白的已充分表征的 Foxp3gfp 报告小鼠是一种亚型体，可在 NOD 背景下导致严重加速的自身免疫性糖尿病。尽管 Foxp3gfp NOD 和 C57BL/6 小鼠中天然 Treg 细胞发育和体外功能没有显着改变，但炎症环境中的 Treg 细胞功能受到干扰，并且 TGFβ 诱导的 Treg 细胞发育减少。 Foxp3gfp 无法与组蛋白乙酰转移酶 Tip60、组蛋白脱乙酰酶 HDAC7 和 Ikaros 家族锌指 4 Eos 相互作用，从而导致 Foxp3 乙酰化减少并增强 K48 连接的多泛素化。总的来说，这导致转录格局改变并减少 Foxp3 介导的基因抑制，特别是在标志性 IL-2 启动子处。受控的 Foxp3 驱动的表观遗传修饰的丧失会导致 Treg 细胞不足，从而在易感环境中产生自身免疫。
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 TGFβ-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.
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影响因子：
32.4
作者：
Fontenot, JD;Rasmussen, JP;Rudensky, AY
通讯作者：
Rudensky, AY
影响因子：
32.4
作者：
Hill, Jonathan A.;Feuerer, Markus;Benoist, Christophe
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影响因子：
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作者：
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通讯作者：
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DOI：
10.1073/pnas.0700298104
发表时间：
2007-03-13
影响因子：
11.1
作者：
Li, Bin;Samanta, Arabinda;Greene, Mark I.
通讯作者：
Greene, Mark I.
DOI：
10.1084/jem.20051409
发表时间：
2005-11-21
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Chen Z;Herman AE;Matos M;Mathis D;Benoist C
通讯作者：
Benoist C