Impact of T‐cell‐specific Smad4 deficiency on the development of autoimmune diabetes in NOD mice

Abstract

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.

Consequences of Mutations and Abnormal Expression of SMAD4 in Tumors and T Cells

“… 88 Donghee Kim et al reported that loss of SMAD4 increased the number of activated/memory CD4 + T cell and elevated proliferation potential of effector T cells, and dysregulated T cell activation, which promoted the progress of autoimmune diabetes and the incidence of the disease. 85 These results indicated that SMAD4 in T cells plays critical role in immune response affecting the development of SS in NOD mice.…”

“… 87 Kim et al explored the role of SMAD4 in T cells from the nonobese diabetic mice with an autoimmune disease, and found that SMAD4 plays a protective role in the development of autoimmune Sjogren’s syndrome. 85 , 88 These findings suggest that the development of autoimmune diabetes benefits from SMAD4 deletion in T cells.…”

“… 84 Although SMAD4 deficiency does not affect the survival of T cells significantly, the proliferation, growth, and the TGF-β-induced differentiation of SMAD4-deficient T cells were reported to be impaired. 85 The cytotoxic function of CD8 + T cells is important for the immune response. Generation of memory-precursor of CD8 + T cells was controlled by SMAD4, and its deficiency weakens the response of memory CD8 + T cells, as their cytotoxic function is partially impaired.…”

Desmoglein-4 Deficiency Exacerbates Psoriasiform Dermatitis in Rats While Psoriasis Patients Displayed a Decreased Gene Expression of DSG4

“…However, the precise contribution of Dsg-4 to KC differentiation and proliferation remains to be elucidated. Following this line, it has been shown that Smad4, a transcription factor involved in TGF-β-mediated effects such as cell cycling inhibition and immunoregulation, is required for Dsg-4 transcription and, most important, is decreased in PSO ( 38 – 40 ). Although, in our work, Dsg-4 deficiency did not affect TGF-β mRNA levels, TGF-β/IL-17 ratio may favor inflammation.…”

Smad4 in T cells plays a protective role in the development of autoimmune Sjögren's syndrome in the nonobese diabetic mouse

“…These mice exhibited typical features of SS, including increased T cell infiltration into lacrimal glands and increased levels of circulating autoantibodies. In addition, the development of diabetes was also accelerated in these mice [ 31 ].…”