Abstract
Autoimmune diabetes is a consequence of immune-cell infiltration and destruction of pancreatic β-cells in the islets of Langerhans. We analyzed the cellular composition of the insulitic lesions in the autoimmune-prone non-obese diabetic (NOD) mouse and observed a peak in recruitment of plasmacytoid dendritic cells (pDCs) to NOD islets around 8–9 weeks of age. This peak coincides with increased spontaneous expression of type-1-IFN response genes and CpG1585 induced production of IFN-α from NOD islets. The transcription factor E2-2 is specifically required for the maturation of pDCs, and we show that knocking out E2-2 conditionally in CD11c+ cells leads to a reduced recruitment of pDCs to pancreatic islets and reduced CpG1585 induced production of IFN-α during insulitis. As a consequence, insulitis has a less aggressive expression profile of the Th1 cytokine IFN-γ and a markedly reduced diabetes incidence. Collectively, these observations demonstrate a disease-promoting role of E2-2 dependent pDCs in the pancreas during autoimmune diabetes in the NOD mouse.
Highlights
Type-1-diabetes (T1D) is an immune-mediated disease caused by insufficient insulin production from the pancreas
We investigated if the reduction of plasmacytoid dendritic cells (DCs) (pDCs) in the NOD.E2-2 conditional knock-out (CKO) mice would affect the cellular composition of insulitis as well as the cytokine profile of the infiltrated pancreatic islets
Several studies have investigated the role of pDCs in the development of autoimmune diabetes and both disease promoting and inhibiting roles of this cell subset have been suggested
Summary
Type-1-diabetes (T1D) is an immune-mediated disease caused by insufficient insulin production from the pancreas. PDCs have been reported to play a regulatory role in T1D [11,12,13] and during progressive insulitis in animal models of diabetes [14,15,16,17,18]. This dual role of pDCs in autoimmune diabetes may be explained by the diverging abilities of activated pDCs to either stimulate or inhibit immune reactions by presenting antigen and producing IFN-I or by producing tolerogenic enzymes and cytokines, respectively (reviewed in [19, 20])
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