Insm1 regulates mTEC development and immune tolerance  

作　　者：Weihua Tao Zhihuan Ye Yiqiu Wei Jianxue Wang Weixin Yang Guoxing Yu Jieyi Xiong Shiqi Jia 

机构地区：[1]The First Affiliated Hospital of Jinan University,Guangzhou,China [2]The Guangdong-Hong Kong-Macao Joint University Laboratory of Metabolic and Molecular Medicine,Jinan University,Guangzhou,China [3]The Institute of Clinical Medicine,Jinan University,Guangzhou,China [4]Key Lab of Guangzhou Basic and Translational Research of Pan-Vascular Diseases,Guangzhou,China [5]Max Delbrück Center for Molecular Medicine in the Helmholtz Association,Berlin,Germany [6]VIB-KU Leuven Center for Cancer Biology,Leuven,Belgium

出　　处：《Cellular & Molecular Immunology》2023年第12期1472-1486,共15页中国免疫学杂志（英文版）

基　　金：supported by the National Natural Science Foundation of China(31970856);the Clinical Frontier Technology Program of the First Affiliated Hospital of Jinan University(JNU1AF-CFTP-2022-a01236);the Science and Technology Program of Guangzhou(202201020042).

摘　　要：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.

关 键 词：Medullary thymic epithelial cells(mTECs) Mimetic cells Tissue-restricted antigens(TRAs) Insulinoma-associated protein 1(lnsm1) AUTOIMMUNITY Autoimmune regulator(Aire) 

分 类 号：R392[医药卫生—免疫学]