Lymphotoxin Signal Promotes Thymic Organogenesis by Eliciting RANK Expression in the Embryonic Thymic Stroma
Lymphotoxin Signal Promotes Thymic Organogenesis by Eliciting RANK Expression in the Embryonic Thymic Stroma
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DOI：
10.4049/jimmunol.1003533
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发表时间：
2011-05-01
影响因子：
4.4
通讯作者：
Matsumoto, Mitsuru
中科院分区：
文献类型：
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作者：
Mouri, Yasuhiro;Yano, Masashi;Matsumoto, Mitsuru
最近发现，由TNFR超家族成员介导的信号，包括淋巴毒素-β受体(LT-beta R)、核因子-kappaB受体激活剂(RANK)和CD40，在组织建立自我耐受所需的髓质胸腺上皮细胞(MTECs)的完整性方面发挥着至关重要的作用。然而，在mTEC分化过程中，负责单个和多个TNFR超家族成员独特和协同作用的机制细节仍然是个谜。在这项研究中，我们发现LTβR信号上调了胸腺基质中RANK的表达，从而促进了对mTEC分化所必需的RANK配体的可获得性。在双缺乏LTβR和RANK信号的小鼠中，观察到胸腺器官发生的夸大缺陷，这突显了LTβR和RANK信号对于mTEC最佳分化的合作。相反，我们观察到LTβR和CD40信号之间几乎没有协同作用。因此，LTβR信号在促进mTEC组织RANK活性方面表现出一种新颖而独特的功能，表明多种细胞因子信号介导的胸腺器官发生与自身免疫的控制有关。免疫学杂志，2011,186：5047-5057。
It has recently become clear that signals mediated by members of the TNFR superfamily, including lymphotoxin-beta receptor (LT beta R), receptor activator for NF-kappa B (RANK), and CD40, play essential roles in organizing the integrity of medullary thymic epithelial cells (mTECs) required for the establishment of self-tolerance. However, details of the mechanism responsible for the unique and cooperative action of individual and multiple TNFR superfamily members during mTEC differentiation still remain enigmatic. In this study, we show that the LT beta R signal upregulates expression of RANK in the thymic stroma, thereby promoting accessibility to the RANK ligand necessary for mTEC differentiation. Cooperation between the LT beta R and RANK signals for optimal mTEC differentiation was underscored by the exaggerated defect of thymic organogenesis observed in mice doubly deficient for these signals. In contrast, we observed little cooperation between the LT beta R and CD40 signals. Thus, the LT beta R signal exhibits a novel and unique function in promoting RANK activity for mTEC organization, indicating a link between thymic organogenesis mediated by multiple cytokine signals and the control of autoimmunity. The Journal of Immunology, 2011, 186: 5047-5057.