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 language | English |
|---|---|
| Pages (from-to) | 2425-2438 |
| Number of pages | 14 |
| Journal | Journal of Experimental Medicine |
| Volume | 211 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - 2014 |
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ASJC Scopus subject areas
- Immunology
- Immunology and Allergy
- Medicine(all)
Cite this
Limitation of immune tolerance-inducing thymic epithelial cell development by Spi-B-mediated negative feedback regulation. / Akiyama, Nobuko; Shinzawa, Miho; Miyauchi, Maki; Yanai, Hiromi; Tateishi, Ryosuke; Shimo, Yusuke; Ohshima, Daisuke; Matsuo, Koichi; Sasaki, Izumi; Hoshino, Katsuaki; Wu, Guoying; Yagi, Shintaro; Inoue, Jun ichiro; Kaisho, Tsuneyasu; Akiyama, Taishin.
In: Journal of Experimental Medicine, Vol. 211, No. 12, 2014, p. 2425-2438.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Limitation of immune tolerance-inducing thymic epithelial cell development by Spi-B-mediated negative feedback regulation
AU - Akiyama, Nobuko
AU - Shinzawa, Miho
AU - Miyauchi, Maki
AU - Yanai, Hiromi
AU - Tateishi, Ryosuke
AU - Shimo, Yusuke
AU - Ohshima, Daisuke
AU - Matsuo, Koichi
AU - Sasaki, Izumi
AU - Hoshino, Katsuaki
AU - Wu, Guoying
AU - Yagi, Shintaro
AU - Inoue, Jun ichiro
AU - Kaisho, Tsuneyasu
AU - Akiyama, Taishin
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
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U2 - 10.1084/jem.20141207
DO - 10.1084/jem.20141207
M3 - Article
VL - 211
SP - 2425
EP - 2438
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
SN - 0022-1007
IS - 12
ER -