Impact of T-cell-specific Smad4 deficiency on the development of autoimmune diabetes in NOD mice.
Type 1 diabetes results from autoimmune-mediated pancreatic beta-cell destruction and transforming growth factor-beta (TGF-β) is known to play a preventive role in type 1 diabetes in non-obese diabetic (NOD) mice. In this study, we investigated the role of Smad4, a key molecule for Smad-dependent TGF-β signaling, in T cells of NOD mice in the pathogenesis of autoimmune diabetes. We generated T-cell-specific Smad4 knockout (Smad4 tKO) NOD mice and assessed the pathological and immunological changes. Smad4 tKO showed earlier onset and increased incidence of diabetes than wild type (WT) NOD mice. Pathological features such as insulitis, anti-glutamic acid decarboxylase auto-antibody levels and serum IFN-γ levels were significantly increased in Smad4 tKO compared with WT NOD mice. Proportion and number of activated/memory CD4+T cell were significantly increased in pancreatic lymph nodes of Smad4 tKO compared with WT NOD mice. However, the proportion and function of regulatory T cells was not different. Effector CD4+T cells from Smad4 tKO were more resistant to suppression by regulatory T cells than effector cells from WT NOD mice. The proliferative potential of effector T cells from Smad4 tKO was significantly elevated compared with WT NOD mice, and activation of sterol regulatory element binding protein-1c (SREBP-1c) in T cells of Smad4 tKO NOD mice was correlated with this proliferative activity. We conclude that Smad4 deletion in T cells of NOD mice accelerated the development of autoimmune diabetes and increased the incidence of the disease by dysregulation of T cell activation at least in part via SREBP-1c activation.
The Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea.
Donghee
D
Kim
The Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea.|College of Pharmacy and Gachon Institute Pharmaceutical Science, Gachon University, Incheon, Korea.
Song Mi
SM
Lee
The Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea.|College of Pharmacy and Gachon Institute Pharmaceutical Science, Gachon University, Incheon, Korea.|Gil Medical Research Institute, Gil Hospital, Incheon, Korea.
Hee-Sook
0000-0002-1166-4932
HS
Jun
D000818:Animals; D001323:Autoantibodies / Q000378:metabolism; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology*; D007156:Immunologic Memory; D018836:Inflammation Mediators / Q000378:metabolism; D007515:Islets of Langerhans / Q000473:pathology; D008198:Lymph Nodes / Q000473:pathology; D008213:Lymphocyte Activation; D008297:Male; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D051901:Smad4 Protein / Q000172:deficiency* / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
D001323:Autoantibodies; D016207:Cytokines; D018836:Inflammation Mediators; D011948:Receptors, Antigen, T-Cell; D051901:Smad4 Protein; D051780:Sterol Regulatory Element Binding Protein 1
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