Goblet cells tune ILC2 activity through a gut-specific response checkpoint

Group 2 innate lymphoid cells (ILC2s) support tissue homeostasis and type 2 inflammation. ILC2s, which are found in many tissues, adapt to local cues to perform tissue-specific functions. Intestinal ILC2s rapidly respond to helminth and protozoan infections via cross-talk with tuft cells, but the mechanism guiding this adaptation remains unclear. Here, we identify Notch signaling, triggered by the ligand Delta-like 1 on goblet cells, as a key regulator of gut ILC2 specialization in mice. Loss of the Notch signaling protein RBPJ did not impair ILC2 development but altered the expression of interleukin-33 (IL-33) and IL-25 receptors (ST2 and IL-17RB, respectively) on gut ILC2s. This increased sensitivity to IL-33, promoted IL-5 and IL-13 production, and drove the expansion of gut eosinophils and goblet cells. Moreover, RBPJ-deficient ILC2s failed to respond to tuft cell–derived IL-25 after Tritrichomonas musculis colonization. Thus, RBPJ-dependent Notch responsiveness in ILC2s regulates intestinal tissue adaptation and primes the tuft cell–ILC2 circuit for intestinal homeostasis.