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. 2019 Oct 9;10:2345. doi: 10.3389/fimmu.2019.02345

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Copyright © 2019 Kobayashi, Takahashi, Takano, Kimura and Hase.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Scheme of differentiation of M cells in PP. (A) RANKL expressed on M-cell inducer (MCi) cells initiate the differentiation of M cells. RANK signaling induces the transcription factor Spi-B and Sox8 parallelly. Spi-B⁺Sox8⁺GP2⁻ cells are immature M cells that have low uptake activity. Sox8 directly induces the expression of GP2. GP2⁺ cells are mature M cells that have high uptake activity. (B) Signaling pathway of M-cell differentiation. RANKL signaling activates canonical NF-κB (p50/RelA) through TRAF6. Canonical NF-κB signaling is required for the activation of non-canonical NF-κB (p52/RelB), which regulates early M-cell marker genes. p52/RelB directly upregulates the expression of transcription factors Spi-B and Sox8. Sox8 directly binds to the Gp2 promoter. Both Spi-B and Sox8 are required for Gp2 expression and M-cell maturation.