Increased IFN-α-Producing Plasmacytoid Dendritic Cells (pDCs) in Human Th1-Mediated Type 1 Diabetes: pDCs Augment Th1 Responses through IFN-α Production

Increasing evidence suggests that type 1 IFN (IFN-alpha beta) is associated with pathogenesis of Th1-mediated type 1 diabetes (T1D). A major source of IFN-alpha beta is plasmacytoid dendritic cells (pDCs). In this study, we analyzed peripheral blood pDC numbers and functions in at-risk, new-onset, and established T1D patients and controls. We found that subjects at risk for T1D and new-onset and established T1D subjects possessed significantly increased pDCs but similar number of myeloid DCs when compared with controls. pDC numbers were not affected by age in T1D subjects but declined with increasing age in control subjects. It was demonstrated that IFN-alpha production by PBMCs stimulated with influenza viruses was significantly higher in T1D subjects than in controls, and IFN-alpha production was correlated with pDC numbers in PBMCs. Of interest, only T1D-associated Coxsackievirus serotype B4 but not B3 induced majority of T1D PBMCs to produce IFN-alpha, which was confirmed to be secreted by pDCs. Finally, in vitro studies demonstrated IFN-alpha produced by pDCs augmented Th1 responses, with significantly greater IFN-gamma-producing CD4(+) T cells from T1D subjects. These findings indicate that increased pDCs and their IFN-alpha beta production may be associated with this Th1-mediated autoimmune disease, especially under certain viral infections linked to T1D pathogenesis.