2. Academic Validation
  3. Human gut M cells resemble dendritic cells and present gluten antigen

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

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. h.clevers@hubrecht.eu.
  • 13 Oncode Institute, Utrecht, The Netherlands. h.clevers@hubrecht.eu.
  • 14 The Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands. h.clevers@hubrecht.eu.
  • 15 Institute of Human Biology (IHB), Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland. h.clevers@hubrecht.eu.
  • # 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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