Title: Tuft-Cell-Derived Leukotrienes Drive Rapid Anti-helminth Immunity in the Small Intestine but Are Dispensable for Anti-protist Immunity
Author: John W. McGinty, Hung-An Ting, Tyler E. Billipp, Marija S. Nadjsombati, Danish M. Khan, Nora A. Barrett, Hong-Erh Liang, Ichiro Matsumoto, Jakob von Moltke
Abstract: Helminths, allergens, and certain protists induce type 2 immune responses, but theunderlying mechanisms of immune activation remain poorly understood. In the smallintestine, chemosensing by epithelial tuft cells results in the activation of group2 innate lymphoid cells (ILC2s), which subsequently drive increased tuft cell frequency.This feedforward circuit is essential for intestinal remodeling and helminth clearance.ILC2 activation requires tuft-cell-derived interleukin-25 (IL-25), but whether additionalsignals regulate the circuit is unclear. Here, we show that tuft cells secrete cysteinylleukotrienes (cysLTs) to rapidly activate type 2 immunity following chemosensing ofhelminth infection. CysLTs cooperate with IL-25 to activate ILC2s, and tuft-cell-specificablation of leukotriene synthesis attenuates type 2 immunity and delays helminth clearance.Conversely, cysLTs are dispensable for the tuft cell response induced by intestinalprotists. Our findings identify an additional tuft cell effector function and suggestcontext-specific regulation of tuft-ILC2 circuits within the small intestine.