Limitation of immune tolerance-inducing thymic epithelial cell development by Spi-B-mediated negative feedback regulation

Nobuko Akiyama, Miho Shinzawa, Maki Miyauchi, Hiromi Yanai, Ryosuke Tateishi, Yusuke Shimo, Daisuke Ohshima, Koichi Matsuo, Izumi Sasaki, Katsuaki Hoshino, Guoying Wu, Shintaro Yagi, Jun ichiro Inoue, Tsuneyasu Kaisho, Taishin Akiyama

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37 Citations (Scopus)

Abstract

Medullary thymic epithelial cells (mTECs) expressing the autoimmune regulator AIRE and various tissue-specific antigens (TSAs) are critical for preventing the onset of autoimmunity and may attenuate tumor immunity. However, molecular mechanisms controlling mTEC development remain elusive. Here, we describe the roles of the transcription factor Spi-B in mTEC development. Spi-B is rapidly up-regulated by receptor activator of NF-κB ligand (RANKL) cytokine signaling, which triggers mTEC differentiation, and in turn up-regulates CD80, CD86, some TSAs, and the natural inhibitor of RANKL signaling, osteoprotegerin (OPG). Spi-B-mediated OPG expression limits mTEC development in neonates but not in embryos, suggesting developmental stage-specific negative feedback regulation. OPGmediated negative regulation attenuates cellularity of thymic regulatory T cells and tumor development in vivo. Hence, these data suggest that this negative RANKL-Spi-B-OPG feedback mechanism finely tunes mTEC development and function and may optimize the trade-off between prevention of autoimmunity and induction of antitumor immunity.

Original languageEnglish
Pages (from-to)2425-2438
Number of pages14
JournalJournal of Experimental Medicine
Volume211
Issue number12
DOIs
Publication statusPublished - 2014

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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  • Cite this

    Akiyama, N., Shinzawa, M., Miyauchi, M., Yanai, H., Tateishi, R., Shimo, Y., Ohshima, D., Matsuo, K., Sasaki, I., Hoshino, K., Wu, G., Yagi, S., Inoue, J. I., Kaisho, T., & Akiyama, T. (2014). Limitation of immune tolerance-inducing thymic epithelial cell development by Spi-B-mediated negative feedback regulation. Journal of Experimental Medicine, 211(12), 2425-2438. https://doi.org/10.1084/jem.20141207