Myeloid dendritic cells maintain Th17 lymphocyte responses during the obstructive phase of experimental biliary atresia (IRC10P.471)

Biliary atresia (BA) is a fibro-inflammatory obstruction of the extrahepatic biliary tree in newborns. It leads to rapid biliary fibrosis and is the most common indication for pediatric liver transplantation. In a model of rhesus rotavirus (RRV)-induced murine BA, plasmacytoid dendritic cells (DC) initiate NK-cell mediated hepatobiliary injury at 3 days post infection (dpi). We hypothesize that myeloid (m)DC coordinate T-cell driven injury during the later obstructive phase of BA. Following RRV injection into CD11c-DTR GFP pups on day 1 of life, frequency of hepatic DC increased 6fold at 12dpi compared with non-infected controls. Expansion of mDCs was accompanied by accumulation of activated CD4 cells in the liver. Plasma IL17A/F levels were increased at 8 and 12dpi (p<0.01) and hepatic IL17A mRNA increased 9fold between 8 and 12dpi. In vitro coculture of DC from 12dpi pups with naive CD4 cells induced IL17A/6 production. DC-depletion following RRV infection with diphtheria toxin reduced the number of hepatic CD4 cells by 3fold which was associated with 2fold decrease in hepatic IL17A mRNA expression and plasma Th17-associated cytokine levels (IL-17F/6) at 12dpi. Importantly, diminished Th17 responses correlated with reduced plasma total bilirubin levels (6.1 vs 11.3mg/dL in control; p<0.01), a biomarker for biliary obstruction. We conclude that mDC maintain hepatic Th17 responses and regulate cholestatic liver injury during the obstructive phase of experimental BA.