Defective T helper response of hepatocyte-stimulated CD4 T cells impairs antiviral CD8 response and viral clearance.
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.
Wiegard
Christiane
C
Department of Medicine I, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
Wolint
Petra
P
Frenzel
Christian
C
Cheruti
Uta
U
Schmitt
Edgar
E
Oxenius
Annette
A
Lohse
Ansgar W
AW
Herkel
Johannes
J
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*
D015704:CD4 Antigens; D016827:CD8 Antigens