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TGF-β-induced CD4+ FoxP3+ regulatory T cell-derived extracellular vesicles modulate Notch1 signaling through miR-449a and prevent collagen-induced arthritis in a murine model

Cellular & Molecular Immunology volume 18, pages 2516–2529 (2021)Cite this article

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Abstract

CD4+FOXP3+ Treg cells are central to the maintenance of self-tolerance and can be defective in autoimmunity. In autoimmune rheumatic diseases, dysfunctional self-tolerance, is to a large extent, caused by insufficient Treg-cell activity. Although nTregs have therapeutic effects in vivo, their relative scarcity and slow rate of in vitro expansion hinder the application of nTreg therapy. It was previously reported that EVs contribute significantly to the suppressive function of FOXP3+ Treg cells. Considering that the stability and plasticity of nTregs remain major challenges in vivo, we established EVs derived from in vitro TGF-β-induced Treg cells (iTreg-EVs) and assessed their functions in a murine model of autoimmune arthritis. The results demonstrated that iTreg-EVs preferentially homed to the pathological joint and efficiently prevented the imbalance in Th17/Treg cells in arthritic mice. Furthermore, we found that miR-449a-5p mediated Notch1 expression modulation and that miR-449a-5p knockdown abolished the effects of iTreg-EVs on effector T cells and regulatory T cells in vitro and in vivo. Taken together, our results show that iTreg-EVs control the inflammatory responses of recipient T cells through miR-449a-5p-dependent modulation of Notch1 and ameliorate the development and severity of arthritis, which may provide a potential cell-free strategy based on manipulating iTreg-EVs to prevent autoimmune arthritis.

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Acknowledgements

We would like to sincerely thank NO at Penn State University Hershey Medical Center for her useful discussion and constructive comments on our paper. This study was supported by the National Key R&D Program of China (2017YFA0105801) and the General Program of the National Natural Science Foundation of China (81871224).

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  1. These authors contributed equally: Jingrong Chen, Feng Huang, Yuluan Hou.

Authors and Affiliations

  1. Department of Clinical Immunology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China

    Jingrong Chen, Feng Huang, Yuluan Hou, Xiaorong Lin, Rongzhen Liang, Xiaojiang Hu, Jun Zhao, Julie Wang & Song Guo Zheng

  2. Department of Internal Medicine, Division of Rheumatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China

    Jingrong Chen

  3. Division of Rheumatology, Department of Medicine, Penn State University Hershey Medical Center, Hershey, PA, USA

    Nancy Olsen

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Conceived and designed the experiment: SGZ Performed the experiments: JRC, XJH, YLH, RZL, JZ, FH, and JW. Processed and analyzed the data: JRC, FH, YLH, and XRL. Wrote and revised the paper: JRC, NO, and SGZ.

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Correspondence to Song Guo Zheng.

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Chen, J., Huang, F., Hou, Y. et al. TGF-β-induced CD4+ FoxP3+ regulatory T cell-derived extracellular vesicles modulate Notch1 signaling through miR-449a and prevent collagen-induced arthritis in a murine model. Cell Mol Immunol 18, 2516–2529 (2021). https://doi.org/10.1038/s41423-021-00764-y

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