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

被引：55

作者：

Akiyama, Nobuko ^{[1
]}

Shinzawa, Miho ^{[1
]}

Miyauchi, Maki ^{[1
]}

Yanai, Hiromi ^{[1
]}

Tateishi, Ryosuke ^{[1
]}

Shimo, Yusuke ^{[1
]}

Ohshima, Daisuke ^{[1
]}

Matsuo, Koichi ^{[2
]}

Sasaki, Izumi ^{[3
]}

Hoshino, Katsuaki ^{[3
,4
,5
]}

Wu, Guoying ^{[6
]}

Yagi, Shintaro ^{[6
]}

Inoue, Jun-ichiro ^{[1
]}

Kaisho, Tsuneyasu ^{[3
,4
]}

Akiyama, Taishin ^{[1
]}

机构：

[1] Univ Tokyo, Inst Med Sci, Div Cellular & Mol Biol, Minato Ku, Tokyo 1088639, Japan

[2] Keio Univ, Grad Sch Med, Lab Cell & Tissue Biol, Shinjuku Ku, Tokyo 1608582, Japan

[3] Osaka Univ, Immunol Frontier Res Ctr, World Premier Int Res Ctr Initiat, Lab Immune Regulat, Suita, Osaka 5650871, Japan

[4] RIKEN, Ctr Integrat Med Sci, Res Ctr Allergy & Immunol, Lab Inflammatory Regulat,Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan

[5] Kagawa Univ, Fac Med, Dept Immunol, Kagawa 7610793, Japan

[6] Univ Tokyo, Grad Sch Agr & Life Sci, Dept Anim Resource Sci, Lab Cellular Biochem,Bunkyo Ku, Tokyo 1138657, Japan

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2014年 / 211卷 / 12期

基金：

日本科学技术振兴机构;

关键词：

PLASMACYTOID DENDRITIC CELL; PRIMARY BILIARY-CIRRHOSIS; TRANSCRIPTION FACTOR; SELF-TOLERANCE; AIRE; MEDULLA; EXPRESSION; SELECTION; FAMILY; STROMA;

D O I：

10.1084/jem.20141207

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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-kappa B 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. OPG-mediated 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.

引用

页码：2425 / 2438

页数：14

共 46 条

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