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*Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322;
Division of Mucosal Immunology, Department of Microbiology and Immunology, University of Tokyo, Tokyo, Japan; and
Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan
Microfold cells (M cells) are specialized epithelial cells situated over Peyer’s patches (PP) and other organized mucosal lymphoid tissues that transport commensal bacteria and other particulate Ags into intraepithelial pockets accessed by APCs. The TNF superfamily member receptor activator of NF-
B ligand (RANKL) is selectively expressed by subepithelial stromal cells in PP domes. We found that RANKL null mice have <2% of wild-type levels of PP M cells and markedly diminished uptake of 200 nm diameter fluorescent beads. Ab-mediated neutralization of RANKL in adult wild-type mice also eliminated most PP M cells. The M cell deficit in RANKL null mice was corrected by systemic administration of exogenous RANKL. Treatment with RANKL also induced the differentiation of villous M cells on all small intestinal villi with the capacity for avid uptake of Salmonella and Yersinia organisms and fluorescent beads. The RANK receptor for RANKL is expressed by epithelial cells throughout the small intestine. We conclude that availability of RANKL is the critical factor controlling the differentiation of M cells from RANK-expressing intestinal epithelial precursor cells.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the National Institutes of Health (DK64730 to I.R.W. and DK64399 supporting the Imaging Core Facility of the Emory Digestive Diseases Research Development Center) and the Crohn’s & Colitis Foundation of America (Senior Research Award to I.R.W.).
2 Address correspondence and reprint requests to Dr. Ifor R. Williams, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Whitehead Bldg. 105D, 615 Michael Street, Atlanta, GA 30322. E-mail address: irwilli{at}emory.edu
3 Abbreviations used in this paper: FAE, follicle-associated epithelium; PP, Peyer’s patch; ILF, isolated lymphoid follicle; M cell, microfold cell; DC, dendritic cell; RANK, receptor activator of NF-B; RANKL, RANK ligand; mTEC, medullary thymic epithelial cell; GST, glutathione S-transferase; UEA-I, Ulex europaeus agglutinin-I; DAPI, 4',6-diamidino-2-phenylindole.
4 The online version of this article contains supplemental material.
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