Limitation of immune tolerance-inducing thymic epithelial cell development by Spi-B-mediated negative feedback regulation.
Limitation of immune tolerance-inducing thymic epithelial cell development by Spi-B-mediated negative feedback regulation.
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DOI：
10.1084/jem.20141207
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发表时间：
2014-11-17
期刊：
影响因子：
--
通讯作者：
Akiyama T
中科院分区：
文献类型：
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作者：
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;Kaisho T;Akiyama T
Akiyama等人。表明转录因子SPI-B被RANKL上调以触发mTEC分化。骨保护素也是由这个信号通路诱导的，作为一个负反馈环来减弱mTEC的发育和胸腺T细胞。髓质胸腺上皮细胞(MTECs)表达自身免疫调节因子AIRE和各种组织特异性抗原(TSA)，对于预防自身免疫的发生至关重要，并可能减弱肿瘤免疫。然而，控制mTEC发展的分子机制仍然难以捉摸。在这里，我们描述了转录因子SPI-B在mTEC发育中的作用。核因子受体激活物B配体(RANKL)细胞因子信号转导迅速上调SPI-B，触发mTEC分化，进而上调CD80CD86、某些TSA和RANKL信号的天然抑制物骨保护素(OPG)。SPI-B介导的OPG表达限制了新生儿mTEC的发育，但不限制胚胎的发育，提示了发育阶段特异性的负反馈调节。OPG介导的负性调节减弱胸腺调节性T细胞的细胞性和体内肿瘤的发展。因此，这些数据表明，这种负的RANKL-SPI-B-OPG反馈机制微调了mTEC的发育和功能，并可能优化自身免疫预防和抗肿瘤免疫诱导之间的权衡。
Akiyama et al. show that transcription factor Spi-B is up-regulated by RANKL to trigger mTEC differentiation. Osteoprotegerin is also induced by this signaling pathway and acts as a negative feedback loop to attenuate mTEC development and thymic T reg cells. 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. 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.
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