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
Division of Cellular and Molecular Biology, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
Laboratory of Cell and Tissue Biology, Graduate School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan.
J Exp Med. 2014 Nov 17;211(12):2425-38. doi: 10.1084/jem.20141207. Epub 2014 Nov 10.
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.
表达自身免疫调节因子AIRE和多种组织特异性抗原（TSA）的髓质胸腺上皮细胞（mTEC）对于预防自身免疫的发生至关重要，并且可能会减弱肿瘤免疫。然而，控制mTEC发育的分子机制仍不清楚。在此，我们描述了转录因子Spi-B在mTEC发育中的作用。Spi-B被NF-κB配体（RANKL）细胞因子信号的受体激活剂迅速上调，后者触发mTEC分化，进而上调CD80、CD86、一些TSA以及RANKL信号的天然抑制剂骨保护素（OPG）。Spi-B介导的OPG表达限制了新生儿而非胚胎中的mTEC发育，提示了发育阶段特异性的负反馈调节。OPG介导的负调节减弱了体内胸腺调节性T细胞的细胞数量和肿瘤发展。因此，这些数据表明这种负性RANKL-Spi-B-OPG反馈机制精细地调节mTEC的发育和功能，并且可能优化预防自身免疫和诱导抗肿瘤免疫之间的平衡。
