ILC2-dependent induction of small intestinal memory and systemic mucosal resilience.

Abstract The IL-25-dependent ILC2-tuft cell circuit drives altered intestinal physiology in response to chronic helminth and protist infections. We optimized an induction regimen with recombinant IL-25 that resulted in long-lasting alterations of the small intestine, which we termed small intestinal memory. This state was characterized by expanded ILC2s and epithelial tuft cells, small intestinal lengthening, and enhanced resistance to helminth infection. ILC2s were necessary for the establishment of small intestinal memory, as this state was induced in Rag-deficient, but not Ragx gc-deficient mice or mice with deletion of IL-17RB on ILCs. ILC2s also maintained small intestinal memory, as this state was rapidly lost upon ILC2 ablation. Transcriptomic analysis revealed dynamic changes in ILC2 identities from IL-25-treated mice, demonstrative of innate memory. Strikingly, although these alterations were induced by IL-25, the ILC2 memory state was sustained in the absence of IL-25, tuft cells, or multiple alarmins like IL-33, TSLP, or IL-18. Finally, we found that small intestinal memory conferred resistance to bacterial and viral infections at distant mucosal sites and notably impacted the metabolic fitness of mice. The induction of enhanced mucosal resilience accompanied by increased metabolic fitness by IL-25 mimics the positive effects of chronic helminth infestation, revealing a mechanistic pathway that might underpin the widespread prevalence of these infections among vertebrates and that could be therapeutically adapted to improve mucosal health.