The Role of TNF-α in the Pathogenesis of Type 1 Diabetes in the Nonobese Diabetic Mouse: Analysis of Dendritic Cell Maturation

$TNF-\alpha$has been linked to the development of type 1 diabetes (T1D). We previously reported that neonatal treatment of nonobese diabetic (NOD) mice with$TNF-\alpha$accelerated the onset of T1D, whereas$TNF-\alpha$blockade in the same time period resulted in a complete absence of diabetes. The mechanisms by which$TNF-\alpha$modulates development of T1D in NOD mice remain unclear. Here we tested the effects of$TNF-\alpha$on the maturation of dendritic cells (DCs) in the NOD mouse. We found that neonatal treatment with$TNF-\alpha$caused an increase in expression of maturation markers on$CD11c^+CD11b^+$DC subpopulations, whereas treatment with anti-$TNF-\alpha$resulted in a decrease in expression of maturation markers in the$CD11c^+CD11b^+$subset. Moreover, neonatal treatment with$TNF-\alpha$resulted in skewed development of a$CD8\alpha^+CD11b^-CD11c^+$DC subset such that$TNF-\alpha$decreases the$CD8\alpha^+CD11c^+$DC subset, increases the$CD11c^+CD11b^+$subset, and causes an increase in the expression of CD40 and CD54 on mature DCs capable of inducing immunity.$Anti-TNF-\alpha-treated$mice had an increase in the$CD8a^+CD11c^+$DCs. Notably, adoptively transferred$na\ddot{i}ve$CD4+T cells from BDC2.5 T cell receptor transgenic mice proliferated in the pancreatic lymph nodes in$TNF-\alpha-treated$NOD mice but not in$anti-TNF-\alpha-treated$mice. Finally, we show that$anti-TNF-\alpha-treated$mice showed immunological tolerance to islet cell proteins. We conclude that$TNF-\alpha$plays an important role in the initiation of T1D in the NOD mouse by regulating the maturation of DCs and, thus, the activation of islet-specific pancreatic lymph node T cells.