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

• Published in: Cellular & molecular immunology Vol. 18; no. 3; pp. 698 - 710
• Main Authors: Zhou, Li, He, Xuemin, Cai, Peihong, Li, Ting, Peng, Rongdong, Dang, Junlong, Li, Yue, Li, Haicheng, Huang, Feng, Shi, Guojun, Xie, Chichu, Lu, Yan, Chen, Yanming
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-03-2021; Nature Publishing Group
• Subjects: 631/250/249/1313/1418; 631/250/251; Animal models; Animals; Antibodies; Autoimmune diseases; Beta cells; Biomedical and Life Sciences; Biomedicine; Cytotoxicity; Diabetes; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Experimental - etiology; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - pathology; Diabetes Mellitus, Experimental - prevention & control; Diabetes Mellitus, Type 1 - etiology; Diabetes Mellitus, Type 1 - metabolism; Diabetes Mellitus, Type 1 - pathology; Diabetes Mellitus, Type 1 - prevention & control; Effector cells; Female; Gene Expression Regulation; Hepatocyte nuclear factor 1; Hepatocyte Nuclear Factor 1-alpha - genetics; Hepatocyte Nuclear Factor 1-alpha - metabolism; Immune system; Immunology; Immunoregulation; Insulin; Insulin-Secreting Cells - immunology; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; Lymphocytes; Lymphocytes T; Male; Medical Microbiology; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Knockout; Microbiology; Pancreas; Streptozocin; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Regulatory - immunology; TOR protein; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism; Vaccine; mTOR and TCF1; type 1 diabetes mellitus; TGF-β; type 1 cytotoxic T cells; induced regulatory T cells
• ISSN: 1672-7681; 2042-0226
• DOI: 10.1038/s41423-020-00623-2

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.