IL-25-induced memory type 2 innate lymphoid cells enforce mucosal immunity
Adaptation of intestinal helminths to vertebrates involved the evolution of strategies to attenuate host tissue damage to support parasite reproduction and dissemination of offspring to the environment. Helminths initiate the IL-25-mediated tuft cell-type 2 innate lymphoid cell (ILC2) circuit that enhances barrier protection of the host, although viable parasites can target and limit this pathway. We used IL-25 alone to create small intestinal adaptation, marked by anatomic and immunologic changes that persisted months after induction. Adaptation was associated with heightened resistance to barrier pathogens, including in the lung, and was enforced by transcriptionally and epigenetically modified effector-memory ILC2s distinct from those described by innate "training"; epithelial stem cells remained unaltered. Despite requiring IL-25 for induction, effector-memory ILC2s maintained an activated state in the absence of multiple alarmins and supported mucosal resilience while avoiding adverse sensitization to chronic inflammation, revealing a pathway for deploying innate immune cells to coordinate a distributed mucosal defense.
Authors
- Ophir D. Klein (ORCID: https://orcid.org/0000-0002-6254-7082)
- Meizi Liu (ORCID: https://orcid.org/0000-0002-7633-3384)
- Sara Viragova (ORCID: https://orcid.org/0000-0003-0598-1445)
- Satoshi Koga (ORCID: https://orcid.org/0000-0003-3218-7255)
- Dario Boffelli (ORCID: https://orcid.org/0000-0003-2529-9056)
- Richard M. Locksley (ORCID: https://orcid.org/0000-0002-5468-6867)
- Michael Diamond (ORCID: https://orcid.org/0000-0002-8791-3165)
- Roberto R. Ricardo-González (ORCID: https://orcid.org/0000-0002-6135-4035)
- Hong-Erh Liang (ORCID: https://orcid.org/0000-0003-0620-7224)
- Claire E. O’Leary (ORCID: https://orcid.org/0000-0001-9052-4593)
- Victor S. Cortez (ORCID: https://orcid.org/0000-0002-9353-0777)
- Dedeepya Vaka (ORCID: https://orcid.org/0000-0001-7951-5514)
- Andrew Schroeder (ORCID: https://orcid.org/0000-0002-8232-7837)
- Nathan Kochhar
Institutions
- Cedars-Sinai Medical Center (US)
- Howard Hughes Medical Institute (US)
- University of California, San Francisco (US)
- Washington University in St. Louis (US)
- Chan Zuckerberg Initiative (United States) (US)
- University of San Francisco (US)
Publication Details
- Journal
- Cell
- Published
- 2025-09-05
- DOI
- https://doi.org/10.1016/j.cell.2025.08.017
- Citations
- 7
- Primary Topic
- IL-33, ST2, and ILC Pathways
- Type
- article
- Field-Weighted Citation Impact
- 5.58