Fezf2 Orchestrates a Thymic Program of Self-Antigen Expression for Immune Tolerance
Fezf2 Orchestrates a Thymic Program of Self-Antigen Expression for Immune Tolerance
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DOI：
10.1016/j.cell.2015.10.013
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发表时间：
2015-11-05
期刊：
影响因子：
64.5
通讯作者：
Takayanagi, Hiroshi
中科院分区：
文献类型：
--
作者：
Takaba, Hiroyuki;Morishita, Yasuyuki;Takayanagi, Hiroshi
对免疫反应的自身耐受性是通过在胸腺髓质上皮细胞（mTEC）中混杂表达组织限制性抗原（TRA）来建立的，导致对自身抗原应答的T细胞的消除。转录调节因子Aire被认为足以诱导TRA，尽管一些迹象表明其他因子可能促进胸腺中TRA的表达。在这里，我们表明，转录因子Fezf2直接调节各种TRA基因的mTECs独立的Aire。在mTECs中缺乏Fezf2的小鼠表现出严重的自身免疫症状，包括产生自身抗体和靶向外周器官的炎性细胞浸润。这些反应不同于在Aire缺陷小鼠中检测到的反应。此外，Fezf2表达和Aire表达受不同的信号通路调节，并促进不同类型蛋白质的表达。因此，两个独立的因素，Fezf2和Aire，允许在胸腺中表达TRA，以确保免疫耐受。
Self-tolerance to immune reactions is established via promiscuous expression of tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs), leading to the elimination of T cells that respond to self-antigens. The transcriptional regulator Aire has been thought to be sufficient for the induction of TRAs, despite some indications that other factors may promote TRA expression in the thymus. Here, we show that the transcription factor Fezf2 directly regulates various TRA genes in mTECs independently of Aire. Mice lacking Fezf2 in mTECs displayed severe autoimmune symptoms, including the production of autoantibodies and inflammatory cell infiltration targeted to peripheral organs. These responses differed from those detected in Aire-deficient mice. Furthermore, Fezf2 expression and Aire expression are regulated by distinct signaling pathways and promote the expression of different classes of proteins. Thus, two independent factors, Fezf2 and Aire, permit the expression of TRAs in the thymus to ensure immune tolerance.