title: 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-γ) 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229-3039, USA.
authors.forename: Celine S
authors.initials: CS
authors.lastname: Lages
authors.forename: Julia
authors.initials: J
authors.lastname: Simmons
authors.forename: Claire A
authors.initials: CA
authors.lastname: Chougnet
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Miethke
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology* / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D001656:Biliary Atresia / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000502:physiology; D002779:Cholestasis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology / Q000502:physiology; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011897:Random Allocation; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*