The role of TNF-α in the pathogenesis of type 1 diabetes in the nonobese diabetic mouse: Analysis of dendritic cell maturation

Abstract

TNF-␣ has been linked to the development of type 1 diabetes (T1D).We previously reported that neonatal treatment of nonobese diabetic (NOD) mice with TNF-␣ accelerated the onset of T1D, whereas TNF-␣ blockade in the same time period resulted in a complete absence of diabetes. The mechanisms by which TNF-␣ modulates development of T1D in NOD mice remain unclear. Here we tested the effects of TNF-␣ on the maturation of dendritic cells (DCs) in the NOD mouse. We found that neonatal treatment with TNF-␣ caused an increase in expression of maturation markers on CD11c ؉ CD11b ؉ DC subpopulations, whereas treatment with anti-TNF-␣ resulted in a decrease in expression of maturation markers in the CD11c ؉ CD11b ؉ subset. Moreover, neonatal treatment with TNF-␣ resulted in skewed development of a CD8␣ ؉ CD11b ؊ CD11c ؉ DC subset such that TNF-␣ decreases the CD8␣ ؉ 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-␣-treated mice had an increase in the CD8␣ ؉ CD11c ؉ DCs. Notably, adoptively transferred naïve CD4 ؉ T cells from BDC2.5 T cell receptor transgenic mice proliferated in the pancreatic lymph nodes in TNF-␣-treated NOD mice but not in anti-TNF-␣-treated mice. Finally, we show that anti-TNF-␣-treated mice showed immunological tolerance to islet cell proteins. We conclude that TNF-␣ 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.immune tolerance ͉ autoreactive T cells ͉ pancreatic lymph nodes T ype 1 diabetes (T1D) in humans and nonobese diabetic (NOD) mice is a complex, multifactorial autoimmune disease in which an islet cell-specific T cell immune response destroys insulin-producing ␤ cells in the islets of Langerhans (1, 2). Genetic susceptibility is determined by multiple genes, and inheritance of susceptibility is a complex polygenic trait. The principal effector mechanism appears to be the action of CD4 ϩ and CD8 ϩ T cells, both T cell subsets being required for transfer of disease in NOD mice (2). In humans and NOD mice, MHC class II genes, the major genetic factor determining susceptibility, are a necessary but not sufficient requirement for full genetic predisposition to T1D (3, 4). The NOD mouse develops spontaneous T1D that shares many characteristics with the human disease (2, 5, 6). Much of our knowledge of the course and pathogenesis of this disease comes from studies in the NOD mouse (2), including several of the principal islet cell autoantigens, the kinetics of development of insulitis and overt diabetes, and the peptide-binding characteristics of the NOD I-A g7 class II MHC molecule (7).TNF-␣ plays multiple roles in the development and function of the immune system. Manipulation of TNF-␣ and its receptors revealed numerous aspects of their functions in autoimmune disease. TNF-␣ promotes up-regulation of adhesion molecules and activation of macrophages and...

Anti–IL-7 receptor-α reverses established type 1 diabetes in nonobese diabetic mice by modulating effector T-cell function

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TNF Receptor 1 Deficiency Increases Regulatory T Cell Function in Nonobese Diabetic Mice

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