Intestinal plasmacytoid dendritic cells preferentially produce interferon lambda [ATAC-seq]

The healthy intestine mounts immune responses to microbiota to maintain homeostasis, which includes basal production of interferon cytokines. Previous work showed that Type III Interferon (IFN-?) stimulates localized pockets of interferon-stimulated genes (ISGs) in the adult mouse intestinal epithelium at homeostasis that provide preemptive protection from viral pathogens. Here, we demonstrate that a major source of homeostatic IFN-? production in the intestine is a population of epithelium-associated plasmacytoid dendritic cells (pDC). These pDC are recruited to the intestine by bacterial microbiota colonization, and pDC depletion or bone marrow reconstitution with IFN-?-deficient pDC results in reduced homeostatic ISGs in the intestinal epithelium. Notably, intestinal pDC preferentially produce IFN-? over Type I IFNs whereas splenic pDC produce more Type I IFNs. Comparison of splenic and intestinal pDC reveal tissue-specific changes in gene expression and genomic accessibility, including evidence of response to transforming growth factor beta (TGF-ß) in the intestine. Isolated gut pDC produce more IFN-? that splenic pDC upon stimulation, and pre-treatment of a human pDC cell line with TGF-ß results in enhanced production of IFN-? upon stimulation. This study implicates pDC as important sources of homeostatic IFN-? in the intestine and defines the role of barrier cytokine TGF-ß in regulating IFN types produced by pDC upon stimulation. Reprogramming of recruited pDC by tissue cytokines may have important implications for balancing effective antimicrobial responses with damaging inflammation at barrier tissues. Overall design: Plasmacytoid dendritic cells were isolated from spleen and small intestinal epithelium of four mice for analysis of genomic accessability by ATACseq.

健康肠道会针对微生物群启动免疫应答以维持稳态，该过程包括干扰素细胞因子的基础产生。既往研究显示，III型干扰素（Type III Interferon, IFN-λ）可在稳态下于成年小鼠肠上皮中刺激干扰素刺激基因（interferon-stimulated genes, ISGs）的局部富集，从而为机体提供针对病毒病原体的先发保护。
本研究证实，肠道稳态下III型干扰素的主要产生来源是一类与上皮细胞相关的浆细胞样树突状细胞（plasmacytoid dendritic cells, pDC）。这些pDC通过细菌微生物群定植被招募至肠道；若耗竭pDC或用III型干扰素缺陷的pDC进行骨髓重建，会导致肠上皮中稳态相关ISGs的表达水平降低。值得注意的是，与脾脏pDC更多产生I型干扰素不同，肠道pDC优先产生III型干扰素。
对脾脏与肠道pDC的比较分析显示，二者存在组织特异性的基因表达与基因组可及性差异，其中包括肠道pDC存在转化生长因子β（transforming growth factor beta, TGF-β）应答的相关证据。体外分离的肠道pDC在受刺激后产生的III型干扰素水平高于脾脏pDC；而用TGF-β预处理人pDC细胞系，可增强其受刺激后III型干扰素的产生能力。
本研究表明pDC是肠道稳态下III型干扰素的重要来源，并明确了屏障细胞因子TGF-β在调控pDC受刺激后产生的干扰素类型中发挥的作用。组织细胞因子对招募而来的pDC进行重编程，或对平衡屏障组织中有效的抗菌应答与病理性炎症具有重要意义。
实验整体设计：从4只小鼠的脾脏与小肠上皮中分离浆细胞样树突状细胞，通过转座酶可及性测序（ATAC-seq）分析其基因组可及性。