Cell Polarization and Epigenetic Status Shape the Heterogeneous Response to Type III Interferons in Intestinal Epithelial Cells.
Cell Polarization and Epigenetic Status Shape the Heterogeneous Response to Type III Interferons in Intestinal Epithelial Cells.
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DOI：
10.3389/fimmu.2017.00671
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发表时间：
2017
影响因子：
7.3
通讯作者：
Köster M
中科院分区：
文献类型：
--
作者：
Bhushal S;Wolfsmüller M;Selvakumar TA;Kemper L;Wirth D;Hornef MW;Hauser H;Köster M
I型和III型干扰素（IFN）是一线抗病毒宿主反应的重要组成部分。虽然存在两种IFN类型的特异性受体，但细胞内信号传导共享相同的Jak-STAT途径。由于其受体表达，IFN-λ反应性主要限于上皮细胞。在这里，我们显示IFN刺激的基因诱导在单细胞水平上比较分析两种IFN类型在肠上皮细胞和小肠类器官中的活性。最初，我们注意到，在低浓度下对两种类型的IFN的反应是基于单细胞决策，决定总细胞内在的抗病毒活性。我们确定组蛋白去乙酰化酶（HDAC）活性是控制IFN-λ而不是IFN-β刺激后IFN刺激基因（ISG）诱导的细胞频率的关键限制因子。一致地，HDAC阻断赋予抗病毒活性至否则无应答的亚群。第二，与I型IFN系统相反，肠上皮细胞的极化强烈增强了它们响应IFN-λ信号传导的能力，并提高了基因诱导的动力学。最后，我们表明，低量IFN在小肠类器官中的ISG诱导的特征在于上皮细胞的分散的异质反应性，并且HDAC活性仅微调IFN-λ活性。本研究提供了对I型和III型IFN的差异反应的全面描述，并证明肠上皮细胞中的细胞极化特异性地增加IFN-λ活性。
Type I and type III interferons (IFNs) are crucial components of the first-line antiviral host response. While specific receptors for both IFN types exist, intracellular signaling shares the same Jak-STAT pathway. Due to its receptor expression, IFN-λ responsiveness is restricted mainly to epithelial cells. Here, we display IFN-stimulated gene induction at the single cell level to comparatively analyze the activities of both IFN types in intestinal epithelial cells and mini-gut organoids. Initially, we noticed that the response to both types of IFNs at low concentrations is based on a single cell decision-making determining the total cell intrinsic antiviral activity. We identified histone deacetylase (HDAC) activity as a crucial restriction factor controlling the cell frequency of IFN-stimulated gene (ISG) induction upon IFN-λ but not IFN-β stimulation. Consistently, HDAC blockade confers antiviral activity to an elsewise non-responding subpopulation. Second, in contrast to the type I IFN system, polarization of intestinal epithelial cells strongly enhances their ability to respond to IFN-λ signaling and raises the kinetics of gene induction. Finally, we show that ISG induction in mini-gut organoids by low amounts of IFN is characterized by a scattered heterogeneous responsiveness of the epithelial cells and HDAC activity fine-tunes exclusively IFN-λ activity. This study provides a comprehensive description of the differential response to type I and type III IFNs and demonstrates that cell polarization in gut epithelial cells specifically increases IFN-λ activity.