title: Defective T helper response of hepatocyte-stimulated CD4 T cells impairs antiviral CD8 response and viral clearance.
abstract: OBJECTIVE
  In hepatitis, hepatocytes gain the ability to express major histocompatibility complex (MHC) class II molecules and to present antigen to CD4 T cells. Here, we investigated whether MHC class II-expressing hepatocytes influence in vitro the differentiation of CD4 T cells and in vivo the T-cell response to and control of viral infection.
  
  
  METHODS
  Class II transactivator-transgenic hepatocytes that constitutively express MHC class II molecules were used to stimulate CD4 T cells in vitro, and the effector response type of the stimulated CD4 T cells was determined. The in vivo relevance of the obtained findings was confirmed by infecting nontransgenic or class II transactivator-transgenic mice with lymphocytic choriomeningitis virus.
  
  
  RESULTS
  MHC II-expressing hepatocytes induced T helper cell (Th) 2 differentiation of uncommitted CD4 T cells and abrogated the ability of previously differentiated Th1 to secrete interferon-gamma, even in the presence of proinflammatory microbial signals. The suppression of Th1 responses by hepatocytes was associated with poor expression levels of Th1-promoting Delta-like Notch ligands. In vivo, MHC II expression by hepatocytes impaired the interferon-gamma production by lymphocytic choriomeningitis virus-specific CD4 and CD8 T cells and prolonged viral persistence.
  
  
  CONCLUSIONS
  By instructing infiltrating CD4 T cells to differentiate into a less inflammatory phenotype, MHC II-expressing hepatocytes seem to impair antiviral CD8 T-cell responses and viral clearance. Thus, hepatocytes may contribute to the chronicity of hepatitis virus infection.
authors.affiliation: Department of Medicine I, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Wiegard
authors.forename: Petra
authors.initials: P
authors.lastname: Wolint
authors.forename: Christian
authors.initials: C
authors.lastname: Frenzel
authors.forename: Uta
authors.initials: U
authors.lastname: Cheruti
authors.forename: Edgar
authors.initials: E
authors.lastname: Schmitt
authors.forename: Annette
authors.initials: A
authors.lastname: Oxenius
authors.forename: Ansgar W
authors.initials: AW
authors.lastname: Lohse
authors.forename: Johannes
authors.initials: J
authors.lastname: Herkel
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016827:CD8 Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D022781:Hepatocytes / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens