肠上皮和 3 型先天淋巴细胞 (ILC3) 之间的双向信号传导可调节分泌动态和 IL-22。
Bi-directional signalling between the intestinal epithelium and type-3 innate lymphoid cells (ILC3) regulates secretory dynamics and IL-22.
发表日期：2023 Nov 10
作者：
Emily Read, Ainize Peña-Cearra, Diana Coman, Geraldine M Jowett, Matthew W H Chung, Isabelle Coales, Sofia Syntaka, Rachel E Finlay, Roser Tachó-Piñot, Sjoerd van Der Post, Umar Naizi, Luke B Roberts, Matthew R Hepworth, Michael A Curtis, Joana F Neves
来源：
Mucosal Immunology
摘要：
3 型先天淋巴细胞 (ILC3) 对局部环境信号作出反应，调节肠道内的稳态并协调免疫。肠上皮是 ILC3 信号传导的重要上游调节剂和下游靶标，然而粘膜组织的复杂性可能会阻碍定义这两个区室之间的特定相互作用的努力。在这里，我们采用小鼠上皮小肠类器官 (SIO) 与 ILC3 的还原共培养系统来揭示肠道稳态的双向信号传导机制。我们报告说，ILC3 诱导肠上皮细胞的整体转录变化，推动分泌杯状细胞特征的富集。我们发现，杯状细胞富集的 SIO 促进 NKp46 ILC3 和 IL-22 表达，这可以反馈诱导 IL-22 介导的上皮转录特征。然而，我们发现该系统中 ILC3 的上皮调节是接触依赖性的，并证明了上皮 Delta-Like-Canonical-Notch-Ligand (Dll) 通过子集特异性 Notch1 介导的激活驱动 ILC3 产生 IL-22 的作用T-bet ILC3。最后，通过干扰 Notch 配体-受体动力学，ILC3 似乎上调上皮 Atoh1，从而扭曲 SIO-ILC3 共培养物中的分泌谱系测定。这项研究概述了肠上皮和 ILC3 之间的两个互补的双向信号模块，它们可能与肠道稳态和疾病相关。版权所有 © 2023。由 Elsevier Inc. 出版。
Type-3 innate lymphoid cells (ILC3) respond to localised environmental cues to regulate homeostasis and orchestrate immunity in the intestine. The intestinal epithelium is an important upstream regulator and downstream target of ILC3 signalling, however the complexity of mucosal tissues can hinder efforts to define specific interactions between these two compartments. Here, we employ a reductionist co-culture system of murine epithelial small intestinal organoids (SIO) with ILC3 to uncover bi-directional signalling mechanisms that underlie intestinal homeostasis. We report that ILC3 induce global transcriptional changes to intestinal epithelial cells, driving the enrichment of secretory goblet cell signatures. We find that SIO enriched for goblet cells promote NKp46+ ILC3 and IL-22 expression, which can feedback to induce IL-22-mediated epithelial transcriptional signatures. However, we show epithelial regulation of ILC3 in this system is contact-dependent and demonstrate a role for epithelial Delta-Like-Canonical-Notch-Ligand (Dll) in driving IL-22 production by ILC3, via subset-specific Notch1-mediated activation of T-bet+ ILC3. Finally, by interfering with Notch ligand-receptor dynamics, ILC3 appear to upregulate epithelial Atoh1 to skew secretory lineage determination in SIO-ILC3 co-cultures. This research outlines two complimentary bi-directional signalling modules between the intestinal epithelium and ILC3, which may be relevant in intestinal homeostasis and disease.Copyright © 2023. Published by Elsevier Inc.