Retinoic acid drives intestine-specific adaptation of effector ILC2s originating from distant sites [bulk RNA-Seq]

Adaptation of immune cells to tissue-specific microenvironments is a crucial process in homeostasis and inflammation. Here, we show that murine effector type 2 innate lymphoid cells (ILC2s) from various organs are equally effective in repopulating ILC2 niches in other anatomical locations where they adapt tissue-specific phenotypes of target organs. Single-cell transcriptomics of ILC2 populations revealed upregulation of retinoic acid (RA) signaling in ILC2s during adaptation to the small intestinal microenvironment, and RA signaling mediated reprogramming of kidney effector ILC2s towards the small intestinal phenotype in vitro and in vivo. Inhibition of intestinal ILC2 adaptation by blocking RA signaling impaired worm expulsion during Strongyloides ratti infection, indicating functional importance of ILC2 tissue imprinting. In conclusion, this study highlights that effector ILC2s retain the ability to adapt to changing tissue-specific microenvironments, enabling them to exert tissue-specific functions, such as promoting control of intestinal helminth infections. To study how tissue-specific factors shape the ILC2s transcriptome originating from kidney, lung and small-intestine lamina propria, we performed bulk RNA sequencing of ILC2s from these organs of naive C57BL/6 mice

免疫细胞对组织特异性微环境的适应，是维持机体稳态与炎症反应中的关键过程。本研究发现，源自不同器官的小鼠效应2型先天淋巴细胞（ILC2s），均可高效重建其他解剖部位的ILC2生态位，并在该处获得靶器官的组织特异性表型。对ILC2群体的单细胞转录组分析显示，在适应小肠微环境的过程中，ILC2内的视黄酸（RA）信号通路出现上调；且RA信号通路可在体外与体内环境中，介导肾脏来源的效应ILC2重编程为小肠表型。通过阻断RA信号通路抑制肠道ILC2的适应过程，会削弱鼠类杆状线虫（Strongyloides ratti）感染后的蠕虫清除能力，这表明ILC2组织印记具有重要的功能意义。综上，本研究证实效应ILC2仍具备适应动态变化的组织特异性微环境的能力，从而能够发挥组织特异性的功能，例如促进肠道蠕虫感染的免疫清除。为探究组织特异性因子如何塑造源自肾脏、肺脏及小肠固有层的ILC2转录组，本研究对未致敏C57BL/6小鼠上述器官来源的ILC2进行了批量RNA测序。