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Insm1 regulates mTEC development and immune tolerance

Item Type:Article
Title:Insm1 regulates mTEC development and immune tolerance
Creators Name:Tao, W. and Ye, Z. and Wei, Y. and Wang, J. and Yang, W. and Yu, G. and Xiong, J. and Jia, S.
Abstract: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. Insm1 expression is undetectable in most mimetic cell populations derived from mTECs but persists in neuroendocrine mimetic cells. Mutation of Insm1 in mice downregulated Aire expression, 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.
Keywords:Medullary Thymic Epithelial Cells (mTECs), Mimetic Cells, Tissue-Restricted Antigens (TRAs), Insulinoma-Associated Protein 1 (Insm1), Autoimmunity, Autoimmune Regulator (Aire), Animals, Mice
Source:Cellular and Molecular Immunology
Publisher:Springer Nature
Page Range:1472-1486
Date:December 2023
Official Publication:https://doi.org/10.1038/s41423-023-01102-0
PubMed:View item in PubMed

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