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Regulatory T cells control the CD8 adaptive immune response at the time of ductal obstruction in experimental biliary atresia.

ABSTRACT: CD8 T-lymphocytes are effector cells of cholangiocyte injury in human and in rhesus rotavirus (RRV)-induced experimental biliary atresia (BA). Here we hypothesize that neonatal deficiency in CD25(+) CD4(+) regulatory T cells (Tregs) leads to aberrant activation of hepatic T-lymphocytes in BA. We found that adoptive transfer of total CD4 cells, but not of CD25-depleted CD4 cells, prior to RRV inoculation reduced expansion of CD8 cells, plasma bilirubin levels, ductal inflammation, and bile duct epithelial injury at 7 days postinfection (dpi) compared with age-matched infected controls without adoptive transfer. Searching for mechanisms, we found that in vitro production of interferon-gamma (IFN-?) by naïve CD8 cells upon polyclonal stimulation was enhanced in coculture with hepatic dendritic cells (DCs) from RRV-infected, but not with DCs from noninfected mice, which was correlated with an increased proportion of CD11b(+) myeloid (m)DCs and up-regulation of the costimulatory molecule CD86 on RRV-primed DCs. Furthermore, DC-dependent T-lymphocyte activation was blocked by anti-CD86 antibody in dose-dependent fashion. Importantly, expression of CD86 on mDCs was down-regulated by Tregs in vitro, and adoptive transfer of Treg-containing CD4 cells decreased expression of CD86 on hepatic mDCs at 7 dpi. On the contrary, in mice resistant to experimental BA, CD25+ cell depletion aggravated bile duct injury at 12 dpi after RRV inoculation, as plasma bilirubin levels were elevated by >20-fold compared with nondepleted infected controls. Increased susceptibility to hepatobiliary injury in Treg-depleted mice was linked to hepatic CD8 expansion and enhanced stimulatory capacity of hepatic DCs.Activation of hepatic T-lymphocytes driving biliary obstruction in BA is regulated by mDCs by way of CD86-dependent costimulation and is susceptible to inhibition by Tregs.

SUBMITTER: Lages CS

PROVIDER: S-EPMC3380144 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Regulatory T cells control the CD8 adaptive immune response at the time of ductal obstruction in experimental biliary atresia.

Lages Celine S CS Simmons Julia J Chougnet Claire A CA Miethke Alexander G AG

Hepatology (Baltimore, Md.) 20120606 1

<h4>Unlabelled</h4>CD8 T-lymphocytes are effector cells of cholangiocyte injury in human and in rhesus rotavirus (RRV)-induced experimental biliary atresia (BA). Here we hypothesize that neonatal deficiency in CD25(+) CD4(+) regulatory T cells (Tregs) leads to aberrant activation of hepatic T-lymphocytes in BA. We found that adoptive transfer of total CD4 cells, but not of CD25-depleted CD4 cells, prior to RRV inoculation reduced expansion of CD8 cells, plasma bilirubin levels, ductal inflammati ...[more]

PMID: 22334397

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Project description:Background & aimsBiliary atresia (BA) results from a neonatal inflammatory and fibrosing obstruction of bile ducts of unknown etiology. Although the innate immune system has been linked to the virally induced mechanism of disease, the role of inflammasome-mediated epithelial injury remains largely undefined. Here, we hypothesized that disruption of the inflammasome suppresses the neonatal proinflammatory response and prevents experimental BA.MethodsWe determined the expression of key inflammasome-related genes in livers from infants at diagnosis of BA and in extrahepatic bile ducts (EHBDs) of neonatal mice after infection with rotavirus (RRV) immediately after birth. Then, we determined the impact of the wholesale inactivation of the genes encoding IL-1R1 (Il1r1-/-), NLRP3 (Nlrp3-/-) or caspase-1 (Casp1-/-) on epithelial injury and bile duct obstruction.ResultsIL1R1, NLRP3 and CASP1 mRNA increased significantly in human livers at the time of diagnosis, and in EHBDs of RRV-infected mice. In Il1r1-/- mice, the epithelial injury of EHBDs induced by RRV was suppressed, with dendritic cells unable to activate natural killer cells. A similar protection was observed in Nlrp3-/- mice, with decreased injury and inflammation of livers and EHBDs. Long-term survival was also improved. In contrast, the inactivation of the Casp1 gene had no impact on tissue injury, and all mice died. Tissue analyses in Il1r1-/- and Nlrp3-/- mice showed decreased populations of dendritic cells and natural killer cells and suppressed expression of type-1 cytokines and chemokines.ConclusionsGenes of the inflammasome are overexpressed at diagnosis of BA in humans and in the BA mouse model. In the experimental model, the targeted loss of IL-1R1 or NLRP3, but not of caspase-1, protected neonatal mice against RRV-induced bile duct obstruction.Lay summaryBiliary atresia is a severe inflammatory and obstructive disease of bile ducts occurring in infancy. Although the cause is unknown, activation of the innate and adaptive immune systems injures the bile duct epithelium. In this study we found that patients' livers had increased expression of inflammasome genes. Using mice engineered to inactivate individual inflammasome genes, the epithelial injury and bile duct obstruction were prevented by the loss of Il1r1 or Nlrp3, with a decreased activation of natural killer cells and expression of cytokines and chemokines. In contrast, the loss of Casp1 did not change the disease phenotype. Combined, the findings point to a differential role of inflammasome gene products in the pathogenic mechanisms of biliary atresia.

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Regulatory T cells control the CD8 adaptive immune response at the time of ductal obstruction in experimental biliary atresia.

Publications

Regulatory T cells control the CD8 adaptive immune response at the time of ductal obstruction in experimental biliary atresia.

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