A neuroepithelial rheostat controls enteric type 1 and type 2 immunity [scRNA-seq]

The nervous and immune systems cooperate to regulate mucosal barrier integrity and host defence. Nevertheless, whether enteric neurons establish neuroepithelial interactions to coordinate immunity remains elusive. Here, we identified a neuroepithelial rheostat that differentially controls type 1 and type 2 immunity. Gut epithelial cells displayed type 1 and type 2 alarmins in distinct circadian cycles, and co-expressed vasoactive intestinal peptide (VIP) receptor 1 (VIPR1), a molecule that integrates diurnal neural-derived VIP signals. Chemogenetic modulation of enteric VIPergic neurons led to altered epithelial-derived cytokines and tuft cells. Epithelial-intrinsic deletion of Vipr1 resulted in diminished type 1 immunity signatures, including reduced type 1 alarmins and intra-epithelial lymphocytes (IEL). In contrast, Vipr1 deficiency in epithelial cells led to increased intestinal type 2 immunity, comprising type 2 alarmins, tuft cells and activated group 2 innate lymphoid cells (ILC2). Disruption of these neuroepithelial interactions led to increased susceptibility to bacterial infection, which greatly contrasted with an increased resistance to parasite infection. Our work identifies a neuroepithelial hub that distinctively controls enteric type 1 and type 2 immunity, deciphering a multi-tissue hub that integrates diurnal physiological cues to balance gut immunity and host defence.