Abstract
Intestinal microfold cells (M cells) are an enigmatic lineage of intestinal epithelial cells that initiate mucosal immune responses through the uptake and transcytosis of luminal antigens. The mechanisms of M-cell differentiation are poorly understood, as the rarity of these cells has hampered analysis. Exogenous administration of the cytokine RANKL can synchronously activate M-cell differentiation in mice. Here we show the Ets transcription factor Spi-B was induced early during M-cell differentiation. Absence of Spi-B silenced the expression of various M-cell markers and prevented the differentiation of M cells in mice. The activation of T cells via an oral route was substantially impaired in the intestine of Spi-B-deficient (Spib−/−) mice. Our study demonstrates that commitment to the intestinal M-cell lineage requires Spi-B as a candidate master regulator.
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Acknowledgements
We thank Z. Guo, Y. Obata, Y. Oohara, Y. Fujimura, M. Ohmae, C. Uetake, Y. Usami and S. Kimura for technical support; T. Kawai for electron microscopy analysis; and H. Matsui (Kitasato University) for S. Typhimurium. Supported by RIKEN (T.Kan., D.T. and I.S.), the Kishimoto Foundation (K.Ho., I.S., H.H. and T.Kai.), the Ministry of Education, Culture, Sports, Science and Technology of Japan (21022049 to K.Ha.; 20060033, 21022048 and 21117003 to T.Kai.; and 20113003 to H.O.), the Japan Society for the Promotion of Science (22689017 to K.Ha.; 23790550 to T.Kan.; 21390155 to H.O.; and 20390146, 23390124 and 18590483 to T.Kai.), the Japan Science and Technology Agency (K.Ha.), The Japan Science Society (K.Ha.), The Takeda Science Foundation (H.O.), The Mitsubishi Foundation (H.O.), The Uehara Memorial Foundation (T.Kai.), the US National Institutes of Health (DK64730 to I.R.W.) and the Bill & Melinda Gates Foundation (OPP1006977 to I.R.W.).
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I.R.W., K.Ha. and H.O. conceived of the study; T.Kan. designed and did the experiments, analyzed data and wrote the manuscript; K.Ha. contributed to adoptive-transfer experiments and data analysis; D.T. and Y.K. helped with flow cytometry; S.F. and T.J. helped with experiments involving infection with S. Typhimurium; K.N. and A.S. did expression analyses; K.Ho., I.S., H.H. and T.Kai. generated Spib−/− mice; K.A.K., N.K. and I.R.W. developed the protocol for treatment with RANKL; M.S. and K.T. helped with electron microscopy; O.Y. and T.Kat. provided human PP samples; S.J.M. provided SM1 mice; K.Ha. and I.R.W. edited the manuscript; and H.O. directed the research and edited the manuscript.
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Kanaya, T., Hase, K., Takahashi, D. et al. The Ets transcription factor Spi-B is essential for the differentiation of intestinal microfold cells. Nat Immunol 13, 729–736 (2012). https://doi.org/10.1038/ni.2352
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DOI: https://doi.org/10.1038/ni.2352
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