Tuft cell acetylcholine is released into the gut lumen to promote anti-helminth immunity
Marième Ndjim, Imène Gasmi, Fabien Herbert, Charlène Joséphine, Julie Bas, A. Lamrani, Nathalie Coutry, S. Henry, Valérie S. Zimmermann, Valérie Dardalhon, Marta Campillo Poveda, Evgenia Turtoi, Steeve Thirard, Luc Forichon, Alicia Giordano, Claire Ciancia, Zeinab Homayed, Julie Pannequin, Collette Britton, Eileen Devaney, Tom N. McNeilly, Sylvie Berrard, Andrei Turtoï, Rick M. Maizels, François Gerbe, Philippe Jay
Abstract
Upon parasitic helminth infection, activated intestinal tuft cells secrete interleukin-25 (IL-25), which initiates a type 2 immune response during which lamina propria type 2 innate lymphoid cells (ILC2s) produce IL-13. This causes epithelial remodeling, including tuft cell hyperplasia, the function of which is unknown. We identified a cholinergic effector function of tuft cells, which are the only epithelial cells that expressed choline acetyltransferase (ChAT). During parasite infection, mice with epithelial-specific deletion of ChAT had increased worm burden, fitness, and fecal egg counts, even though type 2 immune responses were comparable. Mechanistically, IL-13-amplified tuft cells release acetylcholine (ACh) into the gut lumen. Finally, we demonstrated a direct effect of ACh on worms, which reduced their fecundity via helminth-expressed muscarinic ACh receptors. Thus, tuft cells are sentinels in naive mice, and their amplification upon helminth infection provides an additional type 2 immune response effector function.