Analysis of the expression of candidate genes for type 1 diabetes susceptibility in T cells.
Type 1 diabetes is characterized by T-cell-mediated autoimmune destruction of pancreatic β-cells. Currently, approximately 50 type 1 diabetes susceptibility genes or chromosomal regions have been identified. However, the functions of type 1 diabetes susceptibility genes in T cells are elusive. In this study, we evaluated the correlation between type 1 diabetes susceptibility genes and T-cell signaling. The expression levels of 22 candidate type 1 diabetes susceptibility genes in T cells from nonobese diabetic (NOD), control C57BL/6 (B6), and NOD-control F1 hybrid mice were analyzed in response to 2 key immunoregulatory cytokines: interleukin-2 (IL-2) and transforming growth factor β (TGF-β). Exogenous gene expression studies were also performed in EL4 and Jurkat E6.1 T-cell lines. Significant differences in the expression of Clec16a, Dlk1, Il2, Ptpn22, Rnls, and Zac1 (also known as Plagl1) were observed in T cells derived from the 3 strains of mice, and TGF-β differentially influenced the expression of Ctla4, Foxp3, Il2, Ptpn22, Sh2b3, and Zac1. We found that TGF-β induced Zac1 expression in both primary T cells and EL4 cells and that exogenous expression of Zac1 and ZAC1 in T-cell lines altered the expression of Il2 and DLK1, respectively. The results of our study indicate the possibility that additional genetic pathways underlying type 1 diabetes susceptibility, including those involving Clec16a, Dlk1, Rnls, Sh2b3, and Zac1 under IL-2 and TGF-β signaling in T cells, may be shared between human and NOD mice.
Department of Molecular Endocrinology, Osaka University Graduate School of Medicine, Suita 565-0871, Japan.
Yuko
Y
Hisanaga-Oishi
Yumiko
Y
Nishiwaki-Ueda
Koji
K
Nojima
Hironori
H
Ueda
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000235:genetics* / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D005260:Female; D020869:Gene Expression Profiling; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D019169:Jurkat Cells; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D013601:T-Lymphocytes / Q000378:metabolism*