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Induced regulatory T cells suppress Tc1 cells through TGF-β signaling to ameliorate STZ-induced type 1 diabetes mellitus

Cellular & Molecular Immunology volume 18, pages 698–710 (2021)Cite this article

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Abstract

Type 1 diabetes mellitus (T1D) is a chronic autoimmune condition in which the immune system destroys insulin-producing pancreatic β cells. In addition to well-established pathogenic effector T cells, regulatory T cells (Tregs) have also been shown to be defective in T1D. Thus, an increasing number of therapeutic approaches are being developed to target Tregs. However, the role and mechanisms of TGF-β-induced Tregs (iTregs) in T1D remain poorly understood. Here, using a streptozotocin (STZ)-induced preclinical T1D mouse model, we found that iTregs could ameliorate the development of T1D and preserve β cell function. The preventive effect was associated with the inhibition of type 1 cytotoxic T (Tc1) cell function and rebalancing the Treg/Tc1 cell ratio in recipients. Furthermore, we showed that the underlying mechanisms were due to the TGF-β-mediated combinatorial actions of mTOR and TCF1. In addition to the preventive role, the therapeutic effects of iTregs on the established STZ-T1D and nonobese diabetic (NOD) mouse models were tested, which revealed improved β cell function. Our findings therefore provide key new insights into the basic mechanisms involved in the therapeutic role of iTregs in T1D.

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Acknowledgements

This work was supported by the National Key R&D Program of China (2017YFA0105803), the general program of the National Natural Science Foundation of China (81770826), the Science and Technology Plan Projects of Guangdong Province (2019B020227003), the Key Special Projects of Medical and Health of Guangzhou City (202007040003), and the 5010 Clinical Research Projects of Sun Yat-sen University (2015015). Y.M.C. designed the experiments and helped write the manuscript. L.Z. and X.M.H. performed most experiments and collected data. P.H.C. and J.L.D. participated in experiments during revision. L.Z., X.M.H., T.L., R.D.P. analyzed the data. Y.L., H.C.L., F.H., G.J.S., and C.C.X. contributed administrative, technical or material support. L.Z. and Y.L. wrote the manuscript. We thank Song Guo Zheng (Professor of Medicine, Department of Internal Medicine, Ohio State University College of Medicine) for sharing his wisdom with us during the course of this research and for providing comments that greatly improved the manuscript. We thank Julie Wang for providing technical support and helping us with the study design.

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Authors and Affiliations

  1. Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, Guangdong, China

    Li Zhou, Xuemin He, Ting Li, Rongdong Peng, Yue Li, Haicheng Li, Guojun Shi & Yanming Chen

  2. Department of Clinical Immunology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, Guangdong, China

    Li Zhou, Peihong Cai, Junlong Dang, Feng Huang, Chichu Xie & Yan Lu

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Zhou, L., He, X., Cai, P. et al. Induced regulatory T cells suppress Tc1 cells through TGF-β signaling to ameliorate STZ-induced type 1 diabetes mellitus. Cell Mol Immunol 18, 698–710 (2021). https://doi.org/10.1038/s41423-020-00623-2

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Keywords

  • type 1 diabetes mellitus
  • induced regulatory T cells
  • type 1 cytotoxic T cells
  • TGF-β
  • mTOR and TCF1

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