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Development of M cells within the follicle‐associated epithelium of Peyer's Patches depends on expression of TRANCE/RANKL by stromal cells

M cells are specialized epithelial cells found in the follicle‐associated epithelium (FAE) covering Peyer's patches (PP). M cells sample small particulate antigens from the intestinal lumen and transport these antigens to intraepithelial pockets found on the basal aspect of M cells. PP from mice lacking B cells (μMT knockout mice) have a marked reduction (over 150‐fold) in the overall number of intestinal M cells, but the specific receptor‐ligand interaction(s) central to promoting normal M cell differentiation within the FAE have not yet been identified. We now report that PP from mice deficient in the TNF superfamily member TRANCE/RANKL (TNFSF11) display a defect in M cell development that is even more pervasive than that of μMT mice. M cells identified by whole mount immunofluorescence microscopy using rhodamine‐conjugated Ulex europaeus lectin (UEA‐1) are essentially absent from PP in the proximal and central portions of the small intestine. Rare UEA‐1+ M cells are present in a few follicles from the most distal PP of TRANCE‐deficient mice, but these M cells don't have the normal radial symmetry of FAE M cells and are instead abnormally clustered near the apex of the dome. The M cell deficiency in the PP of TRANCE‐deficient mice is associated with impaired formation of PP germinal centers and decreased fecal IgA. TRANCE is selectively expressed by subepithelial stromal cells located in the dome area of PP. These findings indicate that local production of TRANCE by PP stromal cells is required for the normal induction and differentiation of M cells within the FAE.