A proinflammatory program of perinatal plasmacytoid dendritic cells activate natural killer (NK) cells to damage the bile duct epithelium in experimental biliary atresia (43.2)

Abstract

Abstract Biliary atresia results from an NK cell-mediated inflammatory injury of the bile duct epithelium with onset in the early postnatal period. Based on key immunoregulatory roles of dendritic cells (DC), we hypothesized that early neonatal DC activation triggers an effector immune response that results in biliary atresia. We tested this hypothesis in a mouse model of rotavirus-induced biliary atresia. Following rotavirus challenge on day 1 of life, viral immunogenic protein NSP3 was detected in hepatic PDCA-1+ plasmacytoid DC (pDC) but not CD11c+ conventional DC (cDC) within 3 days of infection. Hepatic pDC increased 3 fold, while non-pDC (CD11b+CD11c+ cells) decreased 2.5 fold. Rotavirus-naïve perinatal hepatic pDC and cDC spontaneously expressed B7.1/2 (2-3 fold higher than adults), with a much higher increased expression in B7.1/2, IFNγ, and IL-12p40 by pDC after rotavirus challenge. IL-15 was spontaneously expressed by naïve perinatal pDC and increased dramatically after rotavirus infection, but in vitro activation of NK cells required co-culture with both pDC and cDC. Most notably, ablation of pDC decreased the liver population of NK cells and prevented the mucosa injury and obstruction of neonatal bile ducts, leading to improved symptoms and long-term survival. Thus early activation of pDC due upon viral exposure regulates neonatal duct injury and obstruction in biliary atresia.