In the small intestine, chemosensory tuft cells sense parasitic helminths and release IL-25 to activate resident type 2 innate lymphoid cells (ILC2s), which in turn release IL-13, enhancing the host barrier protection. However, the duration of this adaptation and the cells and pathways that sustain it were unknown. In Cell, Cortez et al. find that IL-25 treatment induces effector-memory ILC2s that persist in an activated state, leading to long-term resilience at mucosal barriers. The authors treated mice intraperitoneally with recombinant IL-25, finding induction of persistent small intestinal adaptations by single-cell RNA sequencing (scRNA-seq) and using IL-5–RFP reporter mice. These included intestinal lengthening, induction of IL-13 target genes in epithelia, and expansion of tuft and goblet cells, similar to the adaptations during helminth infection. The authors compared Rag1-deficient mice treated with IL-25 or not and maintained for at least 40 days before infection with Nippostrongylus brasiliensis, concluding that IL-25-conditioned ILC2s have features of immune memory. IL-25-treated mice had higher resistance to mucosal pathogens such as Salmonella typhimurium or SARS-CoV-2. The authors characterized these ILC2s using scRNA-seq and assay for transposase-accessible chromatin sequencing (ATAC-seq), calling them effector-memory ILC2s, finding that they persist without alarmins or tuft cells and that they are distinct from innate trained ILC2s. This work shows a mucosal defense pathway to induce protective innate immune cells against mucosal pathogens.
Original reference: Cell https://doi.org/10.1016/j.cell.2025.08.017 (2025)
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