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In situ conversion of defective Treg into SuperTreg cells to treat advanced IPEX-like disorders in mice

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  • Yongqin Li

    (School of Life Sciences and Technology, Shanghai Tech University
    CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Yuxin Chen

    (School of Life Sciences and Technology, Shanghai Tech University
    CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Shaoshuai Mao

    (School of Life Sciences and Technology, Shanghai Tech University
    CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Ravinder Kaundal

    (Deptartment Immunobiology, Yale University School of Medicine
    Icahn School of Medicine at Mount Sinai)

  • Zhengyu Jing

    (School of Life Sciences and Technology, Shanghai Tech University)

  • Qin Chen

    (School of Life Sciences and Technology, Shanghai Tech University)

  • Xinxin Wang

    (School of Life Sciences and Technology, Shanghai Tech University)

  • Jing Xia

    (School of Life Sciences and Technology, Shanghai Tech University
    CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Dahai Liu

    (Department of Basic Medicine and Biomedical Engineering, School of Stomatology and Medicine, Foshan University)

  • Jianlong Sun

    (School of Life Sciences and Technology, Shanghai Tech University)

  • Haopeng Wang

    (School of Life Sciences and Technology, Shanghai Tech University)

  • Tian Chi

    (School of Life Sciences and Technology, Shanghai Tech University
    Deptartment Immunobiology, Yale University School of Medicine)

Abstract

Mutations disrupting regulatory T (Treg) cell function can cause IPEX and IPEX-related disorders, but whether established disease can be reversed by correcting these mutations is unclear. Treg-specific deletion of the chromatin remodeling factor Brg1 impairs Treg cell activation and causes fatal autoimmunity in mice. Here, we show with a reversible knockout model that re-expression of Brg1, in conjunction with the severe endogenous proinflammatory environment, can convert defective Treg cells into powerful, super-activated Treg cells (SuperTreg cells) that can resolve advanced autoimmunity, with Brg1 re-expression in a minor fraction of Treg cells sufficient for the resolution in some cases. SuperTreg cells have enhanced trafficking and regulatory capabilities, but become deactivated as the inflammation subsides, thus avoiding excessive immune suppression. We propose a simple, robust yet safe gene-editing-based therapy for IPEX and IPEX-related disorders that exploits the defective Treg cells and the inflammatory environment pre-existing in the patients.

Suggested Citation

  • Yongqin Li & Yuxin Chen & Shaoshuai Mao & Ravinder Kaundal & Zhengyu Jing & Qin Chen & Xinxin Wang & Jing Xia & Dahai Liu & Jianlong Sun & Haopeng Wang & Tian Chi, 2020. "In situ conversion of defective Treg into SuperTreg cells to treat advanced IPEX-like disorders in mice," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15836-2
    DOI: 10.1038/s41467-020-15836-2
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