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S100A4 Protein Is Essential for the Development of Mature Microfold Cells in Peyer’s Patches

Kunimura, K;Sakata, D;Tun, X;Uruno, T;Ushijima, M;Katakai, T;Shiraishi, A;Aihara, R;Kamikaseda, Y;Matsubara, K;Kanegane, H;Sawa, S;Eberl, G;Ohga, S;Yoshikai, Y;Fukui, Y;

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-B 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. Copyright 2019 The Author(s). Published by Elsevier Inc. All rights reserved.