Gut Adaptation of Ahr Expression Cell-intrinsically Restricts Group 2 Innate Lymphoid Cell Function

Innate lymphoid cells (ILCs) are important for mucosal immunity. The intestine harbors all ILC subsets; however, how these cells orchestrate each other to achieve immune homeostasis and mount appropriate immunity during infection remains elusive. Here, we show that the adaptation of the aryl hydrocarbon receptor (Ahr) expression in the gut is a key regulatory mode for the host to keep the ILC balance. Among ILCs, Ahr is most highly expressed by gut ILC2, and controls in a positive feedback manner, chromatin accessibility at the Ahr gene locus. Ahr suppresses Gfi1-mediated ST2 expression in ILC2 and expression of ILC2 effector molecules IL-5, IL-13 and amphiregulin in a cell-intrinsic manner. Ablation of Ahr enhances anti-helminth immunity in the gut, while genetic or pharmacological activation of Ahr suppresses ILC2 but enhances ILC3 to protect the host from Citrobacter rodentium infection. Thus, the host regulates the gut ILC2-ILC3 balance by engaging the Ahr pathway to mount appropriate immunity against various pathogens. RNA-seq (8 samples) and ATAC-seq (24 samples) analysis of small and large intestine ILC2s from Ahr wildtype and knockout mice.