Journal
CELL REPORTS
Volume 29, Issue 9, Pages 2823-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2019.10.091
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Funding
- Leading Advanced Projects for Medical Innovation [LEAP JP19gm0010001]
- Core Research for Evolutionary Medical Science and Technology [CREST JP19gm1310005]
- Practical Research Project for Allergic Diseases and Immunology from the Japan Agency for Medical Research and Development (AMED) [JP19ek0410064]
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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-kB 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.
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