Human gut M cells resemble dendritic cells and present gluten antigen

  • Nature. 2025 Dec 10. doi: 10.1038/s41586-025-09829-8.
Daisong Wang  #  1  2 ,  Sangho Lim  #  1  2 ,  Willine J van de Wetering  3 ,  Carmen Lopez-Iglesias  3 ,  Yuu Okura  4 ,  Yuri Teranishi-Ikawa  4 ,  Akihiko Mizoroki  4 ,  Willem Kasper Spoelstra  5 ,  Talya Dayton  1  2  6 ,  Gijs J F van Son  7 ,  Apollo Pronk  8 ,  Niels Smakman  8 ,  Gieneke B C Gonera-de Jong  9 ,  Sebo Withoff  10 ,  Iris H Jonkers  10 ,  Jeroen S van Zon  5 ,  Sander J Tans  5  11 ,  Peter J Peters  3 ,  Johan H van Es  1  2 ,  Hans Clevers  12  13  14  15
Affiliations
  • 1. Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, UMC Utrecht, Utrecht, The Netherlands.
  • 2. Oncode Institute, Utrecht, The Netherlands.
  • 3. The Microscopy CORE Lab, Maastricht University, Maastricht, The Netherlands.
  • 4. Chugai Pharmaceutical, Tokyo, Japan.
  • 5. AMOLF Institute, Amsterdam, The Netherlands.
  • 6. Tissue Biology and Disease Modeling Unit, EMBL, Barcelona, Spain.
  • 7. The Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
  • 8. Department of Surgery, Diakonessenhuis Utrecht and Zeist, Utrecht, The Netherlands.
  • 9. Department of Pediatrics, Wilhelmina Hospital Assen, Assen, The Netherlands.
  • 10. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
  • 11. Department of Bionanoscience, Kavli Institute of Nanoscience Delft, Delft University of Technology, Delft, The Netherlands.
  • 12. Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, UMC Utrecht, Utrecht, The Netherlands. [email protected].
  • 13. Oncode Institute, Utrecht, The Netherlands. [email protected].
  • 14. The Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands. [email protected].
  • 15. Institute of Human Biology (IHB), Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland. [email protected].
  • # Contributed equally.
PMID: 41372409 DOI: 10.1038/s41586-025-09829-8
Abstract

Microfold (M) cells are rare intestinal epithelial cells that reside in the follicle-associated epithelium of Peyer's patches1. M cells transport luminal antigens to submucosal antigen-presenting cells2,3. These insights primarily derive from transmission electron microscopy and studies using genetically modified mice2-4. Here we establish an intestinal Organoid model to study human M cells and reconstruct the differentiation trajectory of M cells through transcriptome profiling. The results indicate that as well as facilitating luminal antigen transport, human M cells also directly present antigens via the class II major histocompatibility complex (MHC-II). Notably, the related enterocytes only express MHC-II in chronic inflammatory states and do not express typical dendritic cell markers. Human M cells physiologically express a gene profile that resembles that of dendritic cells. Similar to dendritic cells, M cell development is induced by RANKL and CSF2 and requires the transcription factors SPIB and RUNX2. HLA-DQ2.5 M cells process and present gluten antigen as demonstrated in organoid-T cell co-culture assays. These findings suggest that M cells may have a central role in coeliac disease.

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