Peyer’s patch M cells organize an epithelial niche that sustains group 3 innate lymphoid cells and IL-22
Abstract Microfold (M) cells transcytose luminal antigens to initiate mucosal adaptive immunity, but their role in organizing innate responses in Peyer’s patches is unclear. Here we showed that Peyer’s patch M cells organized an epithelial–group 3 innate lymphoid cell (ILC3) axis, establishing a spatial niche within the dome epithelium that drove ILC3 localization, proliferation and IL-22 production. We found that epithelial, but not hematopoietic, SPI-B was required for intestinal IgA responses to establish this niche. Single-cell profiling of intestinal SPI-B + epithelial cells revealed that M cells were highly heterogeneous, displaying tissue- and pathogen-specific transcriptional programs. Using subset-specific genetic perturbation and whole-mount imaging, we found that this circuit relied on CCR6-dependent positioning cues and RANK–RANKL signaling to ILC3 to regulate Peyer’s patch ILC3 homeostasis. Together, these findings identified Peyer’s patch M cells as organizers that spatially coordinated innate cell localization, proliferation and cytokine production to maintain mucosal barrier defense.
Authors
- Stephen L. Nutt (ORCID: https://orcid.org/0000-0002-0020-6637)
- Julie Tellier (ORCID: https://orcid.org/0000-0003-2787-8174)
- Zewen Kelvin Tuong (ORCID: https://orcid.org/0000-0002-6735-6808)
- Renae Denman (ORCID: https://orcid.org/0000-0001-9695-8528)
- Daniela Amann‐Zalcenstein (ORCID: https://orcid.org/0000-0003-4928-1846)
- Ellesandra C. Noye (ORCID: https://orcid.org/0000-0003-1300-5129)
- Matthew E. Ritchie (ORCID: https://orcid.org/0000-0002-7383-0609)
- Richard A. Strugnell (ORCID: https://orcid.org/0000-0003-0614-5641)
- Peter T. Bell (ORCID: https://orcid.org/0000-0002-0653-0286)
- James Santiago
- Nicolas Jacquelot (ORCID: https://orcid.org/0000-0003-0282-1892)
- Yue You (ORCID: https://orcid.org/0000-0003-3883-445X)
- Gabrielle T. Belz (ORCID: https://orcid.org/0000-0002-9660-9587)
- Huiyang Yu (ORCID: https://orcid.org/0000-0002-3670-7898)
- M. Zeeshan Chaudhry (ORCID: https://orcid.org/0000-0002-1372-4257)
- B. C. Lee
- Sophie Curio (ORCID: https://orcid.org/0000-0002-7991-9241)
- Verena C. Wimmer (ORCID: https://orcid.org/0000-0002-9931-8179)
- Peter F. Hickey (ORCID: https://orcid.org/0000-0002-8153-6258)
- Philip M. Hansbro (ORCID: https://orcid.org/0000-0002-4741-3035)
- Cyril Seillet (ORCID: https://orcid.org/0000-0002-0941-8679)
- Qiutong Huang (ORCID: https://orcid.org/0000-0002-4556-0605)
- Jaring Schreuder (ORCID: https://orcid.org/0000-0002-7579-0006)
- Wang Cao (ORCID: https://orcid.org/0000-0001-8023-6096)
- Nancy Wang
- Abbey Waddington (ORCID: https://orcid.org/0009-0009-1663-4992)
- Junpeng Ye
Institutions
- University of Technology Sydney (AU)
- The University of Queensland (AU)
- The University of Melbourne (AU)
- Walter and Eliza Hall Institute of Medical Research (AU)
- Centenary Institute (AU)
- Alberta Children's Hospital (CA)
- Peter Doherty Institute (AU)
- Monash University (AU)
Publication Details
- Journal
- Nature Immunology
- Published
- 2026-08-14
- DOI
- https://doi.org/10.1038/s41590-026-02606-3
- Primary Topic
- IL-33, ST2, and ILC Pathways
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Massachusetts Department of Fish and Game
- Australian Research Council
- National Health and Medical Research Council
- Cancer Council NSW