Research Group Immunology, Leibniz Institute on Aging - Fritz Lipmann Institute, 07745 Jena, Germany.
Research Group Immunology, Leibniz Institute on Aging - Fritz Lipmann Institute, 07745 Jena, Germany.
J Autoimmun. 2017 Jul;81:56-67. doi: 10.1016/j.jaut.2017.03.007. Epub 2017 Apr 3.
Medullary thymic epithelial cells (mTECs) contribute to self-tolerance by expressing and presenting peripheral tissue antigens for negative selection of autoreactive T cells and differentiation of natural regulatory T cells. The molecular control of mTEC development remains incompletely understood. We here demonstrate by TEC-specific gene manipulation in mice that the NF-κB transcription factor subunit RelB, which is activated by the alternative NF-κB pathway, regulates development of mature mTECs in a dose-dependent manner. Mice with conditional deletion of Relb lacked mature mTECs and developed spontaneous autoimmunity. In addition, the NF-κB subunits RelA and c-Rel, which are both activated by classical NF-κB signaling, were jointly required for mTEC differentiation by directly regulating the transcription of Relb. Our data reveal a crosstalk mechanism between classical and alternative NF-κB pathways that tightly controls the development of mature mTECs to ensure self-tolerance.
髓质胸腺上皮细胞（mTECs）通过表达和呈递外周组织抗原来促进自身耐受，从而对自身反应性 T 细胞进行阴性选择和天然调节性 T 细胞的分化。mTEC 发育的分子调控仍不完全清楚。我们通过在小鼠中进行 TEC 特异性基因操作证明，NF-κB 转录因子亚基 RelB 通过非经典 NF-κB 途径激活，以剂量依赖的方式调节成熟 mTECs 的发育。条件性缺失 Relb 的小鼠缺乏成熟的 mTECs，并发生自发性自身免疫。此外，经典 NF-κB 信号激活的 NF-κB 亚基 RelA 和 c-Rel 也通过直接调节 Relb 的转录共同调控 mTEC 分化。我们的数据揭示了经典和非经典 NF-κB 途径之间的相互作用机制，该机制可紧密控制成熟 mTECs 的发育，以确保自身耐受。
