CD4+ T-cell help is required for effective CD8+ T cell-mediated resolution of acute viral hepatitis in mice.
Cytotoxic CD8+ T cells are essential for the control of viral liver infections, such as those caused by HBV or HCV. It is not entirely clear whether CD4+ T-cell help is necessary for establishing anti-viral CD8+ T cell responses that successfully control liver infection. To address the role of CD4+ T cells in acute viral hepatitis, we infected mice with Lymphocytic Choriomeningitis Virus (LCMV) of the strain WE; LCMV-WE causes acute hepatitis in mice and is cleared from the liver by CD8+ T cells within about two weeks. The role of CD4+ T-cell help was studied in CD4+ T cell-lymphopenic mice, which were either induced by genetic deficiency of the major histocompatibility (MHC) class II transactivator (CIITA) in CIITA-/- mice, or by antibody-mediated CD4+ cell depletion. We found that CD4+ T cell-lymphopenic mice developed protracted viral liver infection, which seemed to be a consequence of reduced virus-specific CD8+ T-cell numbers in the liver. Moreover, the anti-viral effector functions of the liver-infiltrating CD8+ T cells in response to stimulation with LCMV peptide, notably the IFN-γ production and degranulation capacity were impaired in CIITA-/- mice. The impaired CD8+ T-cell function in CIITA-/- mice was not associated with increased expression of the exhaustion marker PD-1. Our findings indicate that CD4+ T-cell help is required to establish an effective antiviral CD8+ T-cell response in the liver during acute viral infection. Insufficient virus control and protracted viral hepatitis may be consequences of impaired initial CD4+ T-cell help.
Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Tanja
T
Trautmann
Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Jan-Hendrik
JH
Kozik
Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Antonella
A
Carambia
Institute of Microbiology, Swiss Federal Institute of Technology Zurich, Zürich, Switzerland.
Kirsten
K
Richter
Institute of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Timo
T
Lischke
Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Dorothee
D
Schwinge
Institute of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Hans-Willi
HW
Mittrücker
Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Ansgar W
AW
Lohse
Institute of Microbiology, Swiss Federal Institute of Technology Zurich, Zürich, Switzerland.
Annette
A
Oxenius
Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Christiane
C
Wiegard
Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Johannes
J
Herkel
D000208:Acute Disease; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D006505:Hepatitis / Q000276:immunology* / Q000821:virology; D007371:Interferon-gamma / Q000276:immunology; D008099:Liver / Q000276:immunology / Q000821:virology; D008216:Lymphocytic Choriomeningitis / Q000821:virology; D008217:Lymphocytic choriomeningitis virus; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000821:virology
D007371:Interferon-gamma