Navabi Nazanin, Whitt Jordan, Wu Shu-En, Woo Vivienne, Moncivaiz Jessica, Jordan Michael B, Vallance Bruce A, Way Sing Sing, Alenghat Theresa
Division of Immunobiology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Division of Immunobiology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Cell Rep. 2017 May 9;19(6):1165-1175. doi: 10.1016/j.celrep.2017.04.046.
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.
黏膜组织经常与各种有益和致病微生物直接接触，这凸显了协调复杂微生物信号以维持有效的宿主防御的必要性。在此，我们展示了肠道上皮细胞中组蛋白去乙酰化酶3（HDAC3）的表达在应对致病微生物和激活保护性固有免疫方面的重要作用。在共生微生物群的持续刺激下，肠道上皮细胞缺乏HDAC3的小鼠对鼠柠檬酸杆菌更易感。这种受损的宿主防御反映为感染早期上皮内CD8 T细胞产生的IFNγ显著减少。此外，HDAC3对于感染诱导的上皮细胞表达IFNγ诱导因子IL-18是必需的，给予IL-18可恢复驻留CD8 T细胞的IFNγ活性并减少感染。因此，HDAC3介导肠道上皮细胞与驻留淋巴细胞之间的通讯，揭示了表观遗传修饰剂引发的上皮细胞启动可能指导黏膜对抵御致病微生物的宿主防御进行调节。
