Epithelial Histone Deacetylase 3 Instructs Intestinal Immunity by Coordinating Local Lymphocyte Activation.
Epithelial Histone Deacetylase 3 Instructs Intestinal Immunity by Coordinating Local Lymphocyte Activation.
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DOI：
10.1016/j.celrep.2017.04.046
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发表时间：
2017-05-09
期刊：
影响因子：
8.8
通讯作者：
Alenghat T
中科院分区：
文献类型：
--
作者：
Navabi N;Whitt J;Wu SE;Woo V;Moncivaiz J;Jordan MB;Vallance BA;Way SS;Alenghat T
粘液组织经常与各种有益和致病微生物直接接触，这突出了协调复杂微生物信号以维持有效宿主防御的需要。在这里，我们显示了肠上皮细胞表达组蛋白去乙酰化酶3（HDAC 3）在响应病原微生物和激活保护性先天免疫中的重要作用。在肠道上皮细胞中缺乏HDAC 3的小鼠在肠道微生物群的紧张刺激下更容易受到啮齿柠檬酸杆菌的影响。这种受损的宿主防御反应了感染早期上皮内CD 8 + T细胞产生IFNγ的显著减少。此外，HDAC 3对于IFNγ诱导因子IL-18的感染诱导的上皮表达是必需的，并且IL-18的施用恢复了IFNγ对驻留的CD 8 + T细胞的活性并减少了感染。因此，HDAC 3介导肠上皮细胞和常驻淋巴细胞之间的通信，揭示上皮启动表观遗传修饰剂可能直接粘膜调节宿主防御病原微生物。
Mucosal tissues are constantly in direct contact with diverse beneficial and pathogenic microbes, highlighting the need for orchestrating complex microbial signals to sustain effective host defense. Here we show an essential role for intestinal epithelial cell expression of histone deacetylase 3 (HDAC3) in responding to pathogenic microbes and activating protective innate immunity. Mice lacking HDAC3 in intestinal epithelial cells were more susceptible to Citrobacter rodentium when under tonic stimulation by the commensal microbiota. This impaired host defense reflected significantly decreased IFNγ production by intraepithelial CD8+ T cells early during infection. Further, HDAC3 was necessary for infection-induced epithelial expression of the IFNγ-inducing factor IL-18 and administration of IL-18 restored IFNγ activity to resident CD8+ T cells and reduced infection. Thus, HDAC3 mediates communication between intestinal epithelial cells and resident lymphocytes, revealing that epithelial priming by an epigenetic modifier may direct mucosal regulation of host defense against pathogenic microbes.