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


Posted: 2021-09-24 19:00:00
Cell Mol Immunol . 2021 Sep 23. doi: 10.1038/s41423-021-00764-y. Online ahead of print. Affiliations Expand Affiliations 1 Department of Clinical Immunology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. 2 Department of Internal Medicine, Division of Rheumatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. 3 Division of Rheumatology, Department of Medicine, Penn State University Hershey Medical Center, Hershey, PA, USA. 4 Department of Clinical Immunology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. songguozheng2013@yahoo.com. # Contributed equally. Item in Clipboard Jingrong Chen et al. Cell Mol Immunol. 2021. Show details Display options Display options Format Cell Mol Immunol . 2021 Sep 23. doi: 10.1038/s41423-021-00764-y. Online ahead of print. Affiliations 1 Department of Clinical Immunology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. 2 Department of Internal Medicine, Division of Rheumatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. 3 Division of Rheumatology, Department of Medicine, Penn State University Hershey Medical Center, Hershey, PA, USA. 4 Department of Clinical Immunology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. songguozheng2013@yahoo.com. # Contributed equally. Item in Clipboard CiteDisplay options Display options Format 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. Keywords: Arthritis; EVs; MicroRNA; Notch1; Th17; iTreg. © 2021. The Author(s), under exclusive licence to CSI and USTC. References Li Z, Li D, Tsun A, Li B. FOXP3+ regulatory T cells and their functional regulation. Cell Mol Immunol. 2015;12:558–65. - PubMed - PMC - DOI Williams LM, Rudensky AY. Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nat Immunol. 2007;8:277–84. - PubMed - DOI - PMC Miyara M, Ito Y, Sakaguchi S. TREG-cell therapies for autoimmune rheumatic diseases. Nat Rev Rheumatol. 2014;10:543–51. - PubMed - DOI - PMC Liston A, Gray DH. Homeostatic control of regulatory T cell diversity. Nat Rev Immunol. 2014;14:154–65. - PubMed - DOI - PMC Su W, Chen X, Zhu W, Yu J, Li W, Li Y, et al. The cAMP-Adenosine feedback loop maintains the suppressive function of regulatory T cells. J Immunol. 2019;203:1436–46. - PubMed - DOI - PMC Show all 71 references [x] Cite Copy Format: Send To [x]

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