Figure 2
From: Microfold (M) cells: important immunosurveillance posts in the intestinal epithelium
M cells differentiate from Lgr5+ stem cells in the crypts in a receptor activator of nuclear factor-κB ligand (RANKL)- and Spi-B-dependent manner. (a, 1) All epithelial cell lineages, including M cells, develop from Lgr5+ intestinal epithelial stem cells within the crypts.15 (a, 2) In the intestine, RANKL is selectively expressed by the subepithelial stromal cells beneath the follicle-associated epithelia (FAE).18, 19 RANKL controls the differentiation of Lgr5+ stem cell-derived RANK-expressing enterocytes into M cells.15, 20 (a, 3) RANKL also induces the expression of the ETS (E26 transformation-specific) family transcription factor Spi-B.2 The subsequent differentiation of the annexin A5 (ANXA5)+, MARCKS (myristoylated alanine-rich C-kinase substrate)-like protein 1+ immature M cells into functionally mature glycoprotein 2 (GP2)+, tumor necrosis factor alpha-induced protein 2 (TNFAIP2)+, and C-C motif chemokine ligand 9 (CCL9)+ M cells is regulated by intrinsic expression of Spi-B.2, 15, 22 (a, 4) The chemokine CCL20 is specifically expressed by the FAE,34 and in the Peyer’s patches, it mediates the chemoattraction of C-C motif chemokine receptor 6 (CCR6)-expressing lymphocytes and leukocytes towards the FAE.35 When CCL20-CCR6 signalling is impeded, M-cell maturation is likewise impeded.36, 37, 38 Data suggest that a unique subset of CCR6hiCD11cint B cells specifically migrates towards FAE-derived CCL20 and promotes M-cell differentiation.37 However, as M-cell maturation can be induced in an in vitro “gut organoid” model system containing only epithelial cell elements,15 it is plausible that these CCL20-CCR6-mediated lympho-epithelial interactions most likely provide accessory factors that enhance M-cell differentiation. (b) Immunohistochemical analysis of the distribution of RANKL (green, left-hand panel), ANXA5, GP2 (green and red, respectively, upper-middle panel), Spi-B (green, lower-middle panel), and CCL20 (red, right-hand panel) in mouse Peyer’s patches. Dotted lines indicate the boundary of the FAE. Arrows indicate positively immunostained M cells. V, villi. MNP, mononuclear phagocytes; SED, subepithelial dome.
