title: The Role of Regulatory CD4 T Cells in Maintaining Tolerance in a Mouse Model of Autoimmune Hepatitis.
abstract: BACKGROUND
  The role of regulatory CD4 T cells (Treg) in immune-mediated liver disease is still under debate. It remains disputed whether Treg suppress T cell-mediated hepatitis in vivo and whether hepatic regulatory T cells are functional in patients with autoimmune hepatitis.
  
  
  METHODS
  We used TF-OVA mice, which express ovalbumin in hepatocytes, to investigate the impact of Treg in a model of autoimmune hepatitis. Treg isolated from inflamed livers of TF-OVA mice were tested for their functionality in vitro. By employing double transgenic TF-OVAxDEREG (DEpletion of REGulatory T cells) mice we analyzed whether Treg-depletion aggravates autoimmune inflammation in the liver in vivo.
  
  
  RESULTS
  CD25+Foxp3+ CD4 T cells accumulated in the liver in the course of CD8 T cell-mediated hepatitis. Treg isolated from inflamed livers were functional to suppress CD8 T-cell proliferation in vitro. Depletion of Treg in TF-OVAxDEREG mice dramatically amplified T cell-mediated hepatitis. Repeated administration of antigen-specific CD8 T cells led to a second wave of inflammation only after depletion of Treg.
  
  
  CONCLUSIONS
  Our data add to the evidence for an important role of Treg in autoimmune hepatitis and show that Treg reduce the severity of T-cell mediated hepatitis in vivo. They constitute a key immune cell population that actively maintains a tolerogenic milieu in the liver and protects the liver against repeated inflammatory challenges.
authors.affiliation: Dept. of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Ira
authors.initials: I
authors.lastname: An Haack
authors.affiliation: Institute of Cell Biology and Neurobiology, Center for Anatomy, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Derkow
authors.affiliation: Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research Braunschweig, Braunschweig, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Riehn
authors.affiliation: Dept. of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Marc-Nicolas
authors.initials: MN
authors.lastname: Rentinck
authors.affiliation: Dept. of Medicine I for Gastroenterology, Infectious Diseases and Rheumatology/Research Center ImmunoSciences, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Anja A
authors.initials: AA
authors.lastname: Kühl
authors.affiliation: Institute of Cell Biology and Neurobiology, Center for Anatomy, Charité Universitätsmedizin Berlin, Berlin, Germany.|Cluster of Excellence NeuroCure, Charité Universitätsmedizin Berlin, Berlin, Germany.|Department of Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Seija
authors.initials: S
authors.lastname: Lehnardt
authors.affiliation: Dept. of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Eckart
authors.initials: E
authors.lastname: Schott
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D019693:Hepatitis, Autoimmune / Q000276:immunology* / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit