Conditional deletion of histone deacetylase 1 in T cells leads to enhanced airway inflammation and increased Th2 cytokine production.
Conditional deletion of histone deacetylase 1 in T cells leads to enhanced airway inflammation and increased Th2 cytokine production.
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DOI：
10.4049/jimmunol.0903610
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发表时间：
2010-09-15
期刊：
影响因子：
--
通讯作者：
Ellmeier W
中科院分区：
文献类型：
--
作者：
Grausenburger R;Bilic I;Boucheron N;Zupkovitz G;El-Housseiny L;Tschismarov R;Zhang Y;Rembold M;Gaisberger M;Hartl A;Epstein MM;Matthias P;Seiser C;Ellmeier W
染色质修饰，如可逆组蛋白乙酰化，在T细胞发育和功能的调节中起着关键作用。然而，个体组蛋白去乙酰化酶（hdac）在T细胞中的作用尚不清楚。在这篇文章中，我们通过条件基因靶向表明，在体内过敏性气道炎症模型中，T细胞特异性HDAC1缺失导致炎症反应增加。在这种th2型哮喘模型中，hdac1缺陷T细胞小鼠显示出所有关键参数的增加，如嗜酸性粒细胞向肺募集、粘液分泌过多、肺实质炎症和气道阻力增强。这与从患病小鼠中分离的hdac1缺陷T细胞中Th2细胞因子的产生增强有关。在体外极化hdac1缺陷的Th2细胞显示出类似的IL-4表达增强，这在Th2分化培养的第3天就已经很明显了，并且仅限于经历了几轮细胞分裂的T细胞亚群。在离体非刺激CD4+ T细胞中，HDAC1被招募到Il4基因位点，表明直接控制Il4基因位点。我们的数据提供了遗传学证据，证明HDAC1是一种重要的HDAC，通过调节效应T细胞中的细胞因子表达来控制炎症反应的强度。
Chromatin modifications, such as reversible histone acetylation, play a key role in the regulation of T cell development and function. However, the role of individual histone deacetylases (HDACs) in T cells is less well understood. In this article, we show by conditional gene targeting that T cell-specific loss of HDAC1 led to an increased inflammatory response in an in vivo allergic airway inflammation model. Mice with HDAC1-deficient T cells displayed an increase in all critical parameters in this Th2-type asthma model, such as eosinophil recruitment into the lung, mucus hypersecretion, parenchymal lung inflammation, and enhanced airway resistance. This correlated with enhanced Th2 cytokine production in HDAC1-deficient T cells isolated from diseased mice. In vitro-polarized HDAC1-deficient Th2 cells showed a similar enhancement of IL-4 expression, which was evident already at day 3 of Th2 differentiation cultures and restricted to T cell subsets that underwent several rounds of cell divisions. HDAC1 was recruited to the Il4 gene locus in ex vivo isolated nonstimulated CD4+ T cells, indicating a direct control of the Il4 gene locus. Our data provide genetic evidence that HDAC1 is an essential HDAC that controls the magnitude of an inflammatory response by modulating cytokine expression in effector T cells.
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作者：
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DOI：
10.1164/rccm.2110060
发表时间：
2002-08-01
影响因子：
24.7
作者：
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通讯作者：
Adcock, IM