Retinoid X Receptor Gamma Dictates Reactivity of Intestinal Group 2 Innate Lymphoid Cells and Constrains Type 2 Inflammation

In this work we report that retinoid x receptor gamma (Rxrg) was highly expressed in small intestinal ILC2s, but rapidly suppressed by alarming cytokines. Genetic deletion of Rxrg didn’t impact ILC2 development, but significantly facilitated ILC2 responses and type 2 inflammation induced by IL-25 or helminths. RXRγ maintained the expression of its target genes that support cholesterol efflux in ILC2s. Chemical inhibition of HMG-CoA reductase rescued the abnormal responses of RXRγ-deficient ILC2s. Furthermore, RXRγ expression in ILC2s protected the host from the intestinal mastocytosis induced by skin injury. We propose that the dynamic regulation of RXRγ expression and it mediated genomic states functions as a cell-intrinsic circuit to determine ILC2 reactivity in the small intestine. Small intestinal ILC2s were flow-sorted from Rxrg+/+ (WT) or Rxrg-/-(KO) mice at the steady state, or treated with IL-25 or PBS for two days. The cells were then subjected to bulk RNA-seq, ATAC-seq or CUT&Tag-seq as indicated. Libraries were pair-end (150+ 150 bp) sequenced on a Hiseq X Ten (Illumina).