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Insm1 regulates mTEC development and immune tolerance

Cellular & Molecular Immunology volume 20, pages 1472–1486 (2023)Cite this article

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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.

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Acknowledgements

The authors thank Prof. Carmen Birchmeier (Max-Delbrück-Center for Molecular Medicine, Germany) for helpful discussions at the initiation of the project, for sharing the Insm1+/lacZ Insm1+/flox animals and for critical reading of the manuscript. The authors thank Dr. St-Pierre, C (University of Montreal) and Prof. Perreault, C (University of Montreal) for kindly sharing detailed information on TRAs. The authors thank Prof. Diane Mathis (Harvard Medical School) for providing the superenhancer coordinates. The authors thank Prof. Yuanzhi Lu (Department of Pathology, The First Affiliated Hospital of Jinan University) for help in analyzing lymphocyte infiltration.

Funding

This work was 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) and the Science and Technology Program of Guangzhou (202201020042).

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Author notes

  1. These authors contributed equally: Weihua Tao, Zhihuan Ye, Yiqiu Wei.

Authors and Affiliations

  1. The First Affiliated Hospital of Jinan University, Guangzhou, China

    Weihua Tao, Zhihuan Ye, Yiqiu Wei, Jianxue Wang, Weixin Yang, Guoxing Yu & Shiqi Jia

  2. The Guangdong-Hong Kong-Macao Joint University Laboratory of Metabolic and Molecular Medicine, Jinan University, Guangzhou, China

    Weihua Tao, Zhihuan Ye, Yiqiu Wei, Guoxing Yu & Shiqi Jia

  3. The Institute of Clinical Medicine, Jinan University, Guangzhou, China

    Weihua Tao, Zhihuan Ye, Yiqiu Wei, Guoxing Yu & Shiqi Jia

  4. Key Lab of Guangzhou Basic and Translational Research of Pan-Vascular Diseases, Guangzhou, China

    Weihua Tao & Shiqi Jia

  5. Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany

    Jieyi Xiong

  6. VIB-KU Leuven Center for Cancer Biology, Leuven, Belgium

    Jieyi Xiong

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Contributions

WT designed the study and performed the molecular experiments. ZY and YW contributed to the animal experiments, tissue analysis and flow cytometry analysis. ZY, YW, JW, WY, and GY contributed to the molecular, cellular and histological experiments. JX performed and managed the bioinformatic analysis and participated in manuscript preparation. SJ supervised the project, analyzed the data and wrote the manuscript. SJ is the guarantor of this work and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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Correspondence to Jieyi Xiong or Shiqi Jia.

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Tao, W., Ye, Z., Wei, Y. et al. Insm1 regulates mTEC development and immune tolerance. Cell Mol Immunol 20, 1472–1486 (2023). https://doi.org/10.1038/s41423-023-01102-0

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