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A wave of Foxp3+ regulatory T cell accumulation in the neonatal liver plays unique roles in maintaining self-tolerance

Cellular & Molecular Immunology volume 17, pages 507–518 (2020)Cite this article

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Abstract

Newborn animals require tightly regulated local and systemic immune environments to govern the development and maturation of multiple organs/tissues even though the immune system itself is far from mature during the neonatal period. Regulatory T cells (Tregs) are essential for maintaining immune tolerance/homeostasis and modulating inflammatory responses. The features of Tregs in the neonatal liver under steady-state conditions are not well understood. The present study aimed to investigate the phenotype, functions, and significance of neonatal Tregs in the liver. We found a wave of thymus-derived Treg influx into the liver during 1–2 weeks of age. Depletion of these Tregs between days 7 and 11 after birth rapidly resulted in Th1-type liver inflammation and metabolic disorder. More Tregs in the neonatal liver than in the spleen underwent MHC II-dependent activation and proliferation, and the liver Tregs acquired stronger suppressive functions. The transcriptomic profile of these neonatal liver Tregs showed elevated expression of PPARγ and T-bet and features of Tregs that utilize lipid metabolic machinery and are capable of regulating Th1 responses. The accumulation of Tregs with unique features in the neonatal liver is critical to ensure self-tolerance and liver maturation.

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Acknowledgements

We wish to thank Professors Yu Zhang, Jun Zhang, Wenling Han, Ying Wang, Chao Zhong, Xiaoyan Qiu, and Dan Lv (Peking University, China) for critical comments, helpful discussions, and critical reagents. This work was supported by grants from the National Key Research and Development Program of China (2017YFA0104500), the National Natural Science Foundation of China (81471525, 31671244, and 31872734, Q.G.; 81601975, K.Z.), the Foundation for Innovative Research Groups of the National Natural Science Foundation of China (81621001), and the Non-Profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2018PT31039).

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Authors and Affiliations

  1. Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Peking University, Beijing, China

    Mingyang Li, Weijia Zhao, Yifan Wang, Lixue Jin, Gaowen Jin, Xiuyuan Sun, Wei Wang, Ke Wang, Jie Hao, Rong Jin & Qing Ge

  2. Center for Molecular Metabolism, Nanjing University of Science & Technology, No. 364 Building, 200 Xiaolinwei Street, Nanjing, 210094, China

    Xi Xu

  3. Pediatric Diabetes Research Center, Department of Pediatrics, UCSD, La Jolla, CA, USA

    Wenxian Fu

  4. Department of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing, China

    Ying Sun

  5. Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital & Institute of Hematology, Beijing, 100044, China

    Yingjun Chang & Xiaojun Huang

  6. Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China

    Xuyu Zhou

  7. Peking University Medical and Health Analytical Center, Peking University, Beijing, 100191, China

    Hounan Wu

  8. Translational Stem Cell Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China

    Kunshan Zhang

  9. Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, 100191, China

    Qing Ge

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  1. Mingyang Li
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Contributions

Q.G., M.L., and K.Z. designed the research, analyzed the data, and wrote the paper. M.L., W.Z., L.J., and Y.W. performed the research. W.W., K.W., J.H., R.J., X.S., X.X., Y.C., J.G., X.H., Y.S., and W.F. contributed reagents and technical support. H.W. helped with flow cytometry. X.Z. and K.Z. edited the manuscript. All authors reviewed the manuscript.

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Correspondence to Hounan Wu, Kunshan Zhang or Qing Ge.

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Li, M., Zhao, W., Wang, Y. et al. A wave of Foxp3+ regulatory T cell accumulation in the neonatal liver plays unique roles in maintaining self-tolerance. Cell Mol Immunol 17, 507–518 (2020). https://doi.org/10.1038/s41423-019-0246-9

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