Insm1 regulates mTEC development and immune tolerance
Insm1 regulates mTEC development and immune tolerance
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DOI：
10.1038/s41423-023-01102-0
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发表时间：
2023-11-21
影响因子：
24.1
通讯作者：
Jia，Shiqi
中科院分区：
文献类型：
--
作者：
Tao，Weihua;Ye，Zhihuan;Jia，Shiqi
胸腺髓质上皮细胞（mTEC）中自身抗原的表达对于免疫耐受的建立至关重要，但控制大量表达自身抗原的细胞群的产生和维持的调控网络却知之甚少。在这里，我们发现 Insm1 是一种在神经内分泌和神经元细胞中具有已知功能的锌指蛋白，在 mTEC 中与自身免疫调节因子 (Aire) 广泛共表达。Insm1 在大多数源自 mTEC 的模拟细胞群中检测不到，但在神经内分泌模拟细胞中持续存在。小鼠中 Insm1 的突变下调了 Aire 表达，失调了 mTEC 的基因表达程序，并改变了 mTEC 亚群和组织限制性抗原的表达。与这些发现一致的是，Insm1 的缺失导致多个外周组织出现自身免疫反应。我们发现 Insm1 通过与染色质结合来调节 mTEC 中的基因表达。有趣的是，大多数 Insm1 结合位点被 Aire 共同占据，并在超级增强子区域富集。总之，我们的数据证明了 Insm1 在调节建立免疫耐受所需的自身抗原库中的重要作用。
The expression of self-antigens in medullary thymic epithelial cells (mTECs) is essential for the establishment of immune tolerance, but the regulatory network that controls the generation and maintenance of the multitude of cell populations expressing self-antigens is poorly understood. Here, we show that Insm1, a zinc finger protein with known functions in neuroendocrine and neuronal cells, is broadly coexpressed with an autoimmune regulator (Aire) in mTECs.Insm1expression is undetectable in most mimetic cell populations derived from mTECs but persists in neuroendocrine mimetic cells. Mutation ofInsm1in mice downregulatedAireexpression, dysregulated the gene expression program of mTECs, and altered mTEC subpopulations and the expression of tissue-restricted antigens. Consistent with these findings, loss of Insm1 resulted in autoimmune responses in multiple peripheral tissues. We found that Insm1 regulates gene expression in mTECs by binding to chromatin. Interestingly, the majority of the Insm1 binding sites are co-occupied by Aire and enriched in superenhancer regions. Together, our data demonstrate the important role of Insm1 in the regulation of the repertoire of self-antigens needed to establish immune tolerance.