| Summary: | Summary: Intestinal microfold cells (M cells) in Peyer’s patches are a special subset of epithelial cells that initiate mucosal immune responses through uptake of luminal antigens. Although the cytokine receptor activator of nuclear factor-κB ligand (RANKL) expressed on mesenchymal cells triggers differentiation into M cells, other environmental cues remain unknown. Here, we show that the metastasis-promoting protein S100A4 is required for development of mature M cells. S100A4-producing cells are a heterogenous cell population including lysozyme-expressing dendritic cells and group 3 innate lymphoid cells. We found that in the absence of DOCK8, a Cdc42 activator critical for interstitial leukocyte migration, S100A4-producing cells are reduced in the subepithelial dome, resulting in a maturation defect of M cells. While S100A4 promotes differentiation into mature M cells in organoid culture, genetic inactivation of S100a4 prevents the development of mature M cells in mice. Thus, S100A4 is a key environmental cue that regulates M cell differentiation in collaboration with RANKL. : Kunimura et al. find that in the absence of DOCK8, S100A4-producing cells are reduced in the subepithelial dome, resulting in a maturation defect of M cells in Peyer’s patches. In vitro and in vivo studies demonstrate that S100A4 protein is a key environmental factor that promotes M cell maturation. Keywords: intestinal immunity, Peyer's patch, M cell maturation, DOCK8, S100A4-producing cells
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