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Type 3 Innate Lymphoid Cells Direct Goblet Cell Differentiation via the LT–LTβR Pathway during Listeria Infection
The Journal of Immunology ( IF 4.4 ) Pub Date : 2020-06-26 , DOI: 10.4049/jimmunol.2000197
Yaya Pian 1, 2 , Qian Chai 3 , Boyang Ren 1, 4 , Yue Wang 1, 4 , Mengjie Lv 1 , Ju Qiu 5 , Mingzhao Zhu 3, 4
Affiliation  

Key Points ILC3-derived LT and IEC-derived LTβR regulate innate defense against Listeria. LT–LTβR axis increases GC numbers and MUC2 expression during Listeria infection. LTβR signaling and downstream RelB are associated with GC differentiation. As a specialized subset of intestinal epithelial cells (IECs), goblet cells (GCs) play an important role during the antibacterial response via mucin production. However, the regulatory mechanisms involved in GC differentiation and function during infection, particularly the role of immune cell–IEC cross-talk, remain largely unknown. In this study, using Villin∆Ltbr conditional knockout mice, we demonstrate that LTβR, expressed on IECs, is required for GC hyperplasia and mucin 2 (MUC2) expression during Listeria infection for host defense but not homeostatic maintenance in the naive state. Analysis of single gene-deficient mice revealed that the ligand lymphotoxin (LT), but not LIGHT, and type 3 innate lymphoid cells (ILC3s), but not conventional T cells, are required for MUC2-dependent Listeria control. Conditional deficiency of LT in ILC3s further confirmed the importance of LT signals derived from ILC3s. Lack of ILC3-derived LT or IEC-derived LTβR resulted in the defective expression of genes related to GC differentiation but was not correlated with IEC proliferation and cell death, which were found to be normal by Ki-67 and Annexin V staining. In addition, the alternative NF-κB signaling pathway (involving RelB) in IECs was found to be required for the expression of GC differentiation-related genes and Muc2 and required for the anti-Listeria response. Therefore, our data together suggest a previously unrecognized ILC3–IEC interaction and LT–LTβR–RelB signaling axis governing GC differentiation and function during Listeria infection for host defense.

中文翻译:

3 型先天淋巴细胞在李斯特菌感染期间通过 LT-LTβR 通路直接进行杯状细胞分化

关键点 ILC3 衍生的 LT 和 IEC 衍生的 LTβR 调节对李斯特菌的先天防御。LT-LTβR 轴在李斯特菌感染期间增加 GC 数量和 MUC2 表达。LTβR 信号传导和下游 RelB 与 GC 分化相关。作为肠上皮细胞 (IEC) 的一个特殊亚群,杯状细胞 (GC) 在通过粘蛋白产生的抗菌反应过程中发挥着重要作用。然而,感染期间参与 GC 分化和功能的调节机制,特别是免疫细胞-IEC 串扰的作用,在很大程度上仍然未知。在这项研究中,我们使用 Villin∆Ltbr 条件性敲除小鼠证明,在 IEC 上表达的 LTβR 是李斯特菌感染期间 GC 增生和粘蛋白 2 (MUC2) 表达所必需的,用于宿主防御,但不是幼稚状态下的稳态维持。对单基因缺陷小鼠的分析表明,依赖 MUC2 的李斯特菌控制需要配体淋巴毒素 (LT),但不是 LIGHT,和 3 型先天淋巴细胞 (ILC3),但不是常规 T 细胞。ILC3s 中 LT 的条件缺陷进一步证实了来自 ILC3s 的 LT 信号的重要性。缺乏 ILC3 衍生的 LT 或 IEC 衍生的 LTβR 导致与 GC 分化相关的基因表达缺陷,但与 IEC 增殖和细胞死亡无关,通过 Ki-67 和膜联蛋白 V 染色发现这些基因是正常的。此外,发现 IEC 中的替代 NF-κB 信号通路(涉及 RelB)是 GC 分化相关基因和 Muc2 表达所必需的,并且是抗李斯特菌反应所必需的。所以,
更新日期:2020-06-26
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