Type 1 diabetes (T1D) in the non-obese diabetic (NOD) mouse begins with activation of islet-reactive T helper-1 (Th1) cells by dendritic cells (DCs). Since multiple genetic loci contribute to T1D, we evaluated the hypothesis that NOD DCs possess inherent characteristics that contribute to the autoimmune phenotype. When compared to a representative Th1 (C57BL/6) and Th2 (BALB/C) control strain, in vitro generated NOD myeloid DCs matured normally. Functionally, NOD DCs exhibited higher expression of CD80/86 and IL-12 production during stimulation of nai;ve T cells, even in comparison to C57BL/6 DCs, the prototype strain for vigorous, Th1-biased immunity. These features of NOD DCs translated into aberrantly elevated IFN-gamma synthesis, enhanced T-cell proliferation, and heightened CD69 expression. Further, NOR DCs, from an NOD-related, autoimmune-resistant strain, did not display this hyper-responsiveness, suggesting that these abnormalities are genetic features of NOD DCs that are related to disease pathogenesis. Cumulatively, these results indicate that NOD DCs are inherently biased towards abnormally high costimulation and Th1-induction, two features that would be expected to confer activation and persistence of autoreactive T cells.
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