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Histone methyltransferase Nsd2 ensures maternal–fetal immune tolerance by promoting regulatory T-cell recruitment

Cellular & Molecular Immunology volume 19, pages 634–643 (2022)Cite this article

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Abstract

Regulatory T cells (Tregs) are fundamentally important for maintaining systemic immune homeostasis and are also required for immune tolerance at the maternal–fetal interface during pregnancy. Recent studies have suggested that epigenetic regulation is critically involved in Treg development and function. However, the role of H3K36me has not yet been investigated. Here, we found that the H3K36me2 methyltransferase Nsd2 was highly expressed in Tregs. Although loss of Nsd2 did not impair systemic Treg development or function, the level of Tregs at the maternal–fetal interface was significantly decreased in pregnant Nsd2 conditional knockout mice. Consequently, maternal–fetal immune tolerance was disrupted in the absence of Nsd2 in Tregs, and the pregnant mice showed severe fetal loss. Mechanistically, Nsd2 was found to upregulate CXCR4 expression via H3K36me2 modification to promote Treg cell recruitment into the decidua and suppress the anti-fetal immune response. Overall, our data identified Nsd2 as a critical epigenetic regulator of Treg recruitment for maternal–fetal tolerance.

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Acknowledgements

We thank Dr. Haiming Wei and Dr. Bingqing Fu (University of Science and Technology of China) for technical help with the decidual cell preparation and invaluable discussion.

Funding

This study was supported by the National Key R&D Program of China (2018YFC1003900), the National Natural Science Foundation of China (Grant Number 82001653 to LZ and 31970828 to XW) and Jiangsu Outstanding Young Investigator Program (BK20200030).

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  1. These authors contributed equally: Le Zhang, Xuehui Long.

Authors and Affiliations

  1. Department of Immunology, State Key Laboratory of Reproductive Medicine, NHC Key Laboratory of Antibody Technique, Nanjing Medical University, Nanjing, Jiangsu, China

    Le Zhang, Xuehui Long, Yuye Yin, Jun Wang, Huamin Zhu, Jingjing Chen, Yuliang Wang & Xiaoming Wang

  2. Analysis Center, Nanjing Medical University, Nanjing, Jiangsu, China

    Le Zhang

  3. Department of Immunology, Key Laboratory of Immune Microenvironment and Disease, Nanjing Medical University, Nanjing, Jiangsu, China

    Yun Chen & Xiaoming Wang

  4. State Key Laboratory of Reproductive Medicine, Department of Prenatal Diagnosis, Women’s Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Hospital, Nanjing Medical University, Nanjing, Jiangsu, China

    Yun Chen

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LZ, YC, and XW conceptualized the project, designed the experimental approaches, analyzed the data, and prepared the paper. LZ, XL, YY, YW, and JW performed most of the experiments.

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Correspondence to Yun Chen or Xiaoming Wang.

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Zhang, L., Long, X., Yin, Y. et al. Histone methyltransferase Nsd2 ensures maternal–fetal immune tolerance by promoting regulatory T-cell recruitment. Cell Mol Immunol 19, 634–643 (2022). https://doi.org/10.1038/s41423-022-00849-2

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