Retinoic acid drives intestine-specific adaptation of effector ILC2s originating from distant sites [scRNA-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. Overall design: To investigate transcriptional programs sepcific to kidney and SILP ILC2s and those flexible during ILC2 adaptation to the small-intestinal microenvironment, we performed single-cell RNA sequencing of kidney and SILP ILC2s from donor mice and from those of recipient mice. ILC2s from kidney were transferred into alymphoid mice (recipient mice) and analysed after 2 and 8 weeks of transfer