The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance
The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance
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DOI：
10.1016/j.immuni.2008.06.015
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发表时间：
2008-09-19
期刊：
影响因子：
32.4
通讯作者：
Inoue, Jun-ichiro
中科院分区：
文献类型：
--
作者：
Akiyama, Taishin;Shimo, Yusuke;Inoue, Jun-ichiro
胸腺髓质上皮细胞（mTECs）通过表达自身免疫调节因子（Aire）和外周组织特异性自身抗原来建立T细胞自身耐受。然而，mTEC发展的潜在信号在很大程度上仍不清楚。在这里，我们证明了NF-κ B受体激活剂（RANK）和CD 40信号对mTEC发育的重要调控。然而，只有RANK信号是必不可少的mTEC的发展在胚胎发育过程中，在出生后的小鼠，CD 40和RANK信号之间的合作需要mTEC的发展，以成功地建立髓质微环境。体外胎胸腺基质上RANK或CD 40的连接以肿瘤坏死因子相关因子6（TRAF 6）-、NF-κ B诱导激酶（NIK）-和I κ B激酶β（IKK β）-依赖性方式诱导mTEC发育。这些结果表明，RANK和CD 40之间发展依赖于心理阶段的合作促进mTEC的发展，从而建立自我耐受。
Medullary thymic epithelial cells (mTECs) establish T cell self-tolerance through the expression of autoimmune regulator (Aire) and peripheral tissue-specific self-antigens. However, signals underlying mTEC development remain largely unclear. Here, we demonstrate crucial regulation of mTEC development by receptor activator of NF-kappa B (RANK) and CD40 signals. Whereas only RANK signaling was essential for mTEC development during embryogenesis, in postnatal mice, cooperation between CD40 and RANK signals was required for mTEC development to successfully establish the medullary microenvironment. Ligation of RANK or CD40 on fetal thymic stroma in vitro induced mTEC development in a tumor necrosis factor-associated factor 6 (TRAF6)-, NF-kappa B inducing kinase (NIK)-, and I kappa B kinase beta (IKK beta)-dependent manner. These results show that develop mental-stage-dependent cooperation between RANK and CD40 promotes mTEC development, thereby establishing self-tolerance.