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

Hepatology. 2012 Jul;56(1):219-27. doi: 10.1002/hep.25662. Epub 2012 Jun 6.


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.

Conclusion: 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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity / immunology*
  • Adaptive Immunity / physiology
  • Analysis of Variance
  • Animals
  • Biliary Atresia / genetics
  • Biliary Atresia / immunology*
  • Biliary Atresia / pathology
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / physiology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / physiology
  • Cholestasis / genetics
  • Cholestasis / immunology*
  • Cholestasis / pathology
  • Dendritic Cells / immunology
  • Dendritic Cells / physiology
  • Disease Models, Animal
  • Immunohistochemistry
  • Lymphocyte Activation / genetics
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Random Allocation
  • Signal Transduction
  • T-Lymphocytes, Regulatory / immunology*