Daisong Wang, Sangho Lim, Willine J. van de Wetering, Carmen López-Iglesias, Yuu Okura, Yuri Teranishi-Ikawa, Akihiko Mizoroki, Willem Kasper Spoelstra, Talya L. Dayton, Gijs J. F. van Son, Apollo Pronk, Niels Smakman, Gieneke B. C. Gonera-de Jong, Sebo Withoff, Iris H. Jonkers, Jeroen S. van Zon, Sander J. Tans, Peter J. Peters, Johan H. van Es, Hans Clevers
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. An intestinal organoid model recapitulates human microfold (M) cell function and transcriptomic profiling and biochemical assays demonstrate that M cells uptake and present antigens to the immune system via the class II major histocompatibility complex.