Intestinal epithelial tuft cells initiate type 2 mucosal immunity to helminth parasites

Abstract

Epithelial tuft cells secretion of IL-25 is shown to regulate type 2 epithelial responses to helminth parasite infection via an IL-13/IL-4Rα-dependent feedback loop. The 'weep-and-sweep' response to parasitic helminths and allergens, in which parasites are ejected by increased propulsive activity of the gut combined with fluid and mucus secretion, is a manifestation of type 2 (or allergic) immunity involving the activation of group 2 innate lymphoid cells (ILC2s). The epithelium in the small intestine consists of five or more distinct cellular lineages, including tuft cells, whose functions remain unclear. Two papers in this issue of Nature demonstrate a role for tuft cells in the response to parasites. Richard Locksley and colleagues show that tuft cells are the source of the interleukin 25 (IL-25) that is required for activation of ILC2s, ILC2-regulated tuft and goblet cell expansion, and control of parasite infection. Philippe Jay and colleagues show that tuft cells secrete IL-25 via an IL-13/IL-4R -dependent feedback loop. Helminth parasitic infections are a major global health and social burden1. The host defence against helminths such as Nippostrongylus brasiliensis is orchestrated by type 2 cell-mediated immunity2. Induction of type 2 cytokines, including interleukins (IL) IL-4 and IL-13, induce goblet cell hyperplasia with mucus production, ultimately resulting in worm expulsion3,4. However, the mechanisms underlying the initiation of type 2 responses remain incompletely understood. Here we show that tuft cells, a rare epithelial cell type in the steady-state intestinal epithelium5, are responsible for initiating type 2 responses to parasites by a cytokine-mediated cellular relay. Tuft cells have a Th2-related gene expression signature6 and we demonstrate that they undergo a rapid and extensive IL-4Rα-dependent amplification following infection with helminth parasites, owing to direct differentiation of epithelial crypt progenitor cells. We find that the Pou2f3 gene is essential for tuft cell specification. Pou2f3−/− mice lack intestinal tuft cells and have defective mucosal type 2 responses to helminth infection; goblet cell hyperplasia is abrogated and worm expulsion is compromised. Notably, IL-4Rα signalling is sufficient to induce expansion of the tuft cell lineage, and ectopic stimulation of this signalling cascade obviates the need for tuft cells in the epithelial cell remodelling of the intestine. Moreover, tuft cells secrete IL-25, thereby regulating type 2 immune responses. Our data reveal a novel function of intestinal epithelial tuft cells and demonstrate a cellular relay required for initiating mucosal type 2 immunity to helminth infection.