Interleukin-18 Constrains the Intestinal Tuft Cell-Driven Responses During Helminth Infection.

Type 2 immunity at mucosal surfaces is essential for helminth clearance, tissue repair, and barrier maintenance, processes governed by a robust feed-forward circuit between chemosensory tuft cells and group 2 innate lymphoid cells (ILC2s). However, the regulatory mechanisms that calibrate the magnitude and duration of this epithelial immune circuit remain incompletely defined. Here, we identify interleukin-18 (IL-18), a cytokine traditionally associated with type 1 immunity, as a key regulator of tuft cell-mediated type 2 responses during Nippostrongylus brasiliensis (N. brasiliensis) infection. IL-18-deficient (Il18-/-) mice exhibited reduced intestinal worm burden at day 7 post-infection, which correlated with an expansion of tuft cell lineage, increased expression of tuft cell and type 2 response associated genes, and enhanced ILC2 responses. Consistent with these findings, loss of IL-18 receptor (Il18r1-/-) further enhanced succinate-induced tuft cell hyperplasia. Within the intestinal epithelium, tuft cells were found to preferentially express IL-18Rα, suggesting potentially direct responsiveness to IL-18. Using small intestinal organoid models, we demonstrate that IL-18 directly attenuates IL-13-induced tuft cell differentiation, proliferation, and signature gene expression in an IL-18Rα-dependent manner. Mechanistically, pharmacological inhibition of p38 MAPK partially reversed the inhibitory effects of IL-18, identifying p38 signalling as a critical downstream mediator of this regulatory process. Together, these findings reveal that IL-18 functions as a negative feedback signal to constrain tuft cell-associated type 2 epithelial responses during helminth infection, thereby maintaining the balance between protective anti-helminth immunity and mucosal homeostasis.