PLoS ONE (Jan 2014)

CD4+ T-cell help is required for effective CD8+ T cell-mediated resolution of acute viral hepatitis in mice.

  • Tanja Trautmann,
  • Jan-Hendrik Kozik,
  • Antonella Carambia,
  • Kirsten Richter,
  • Timo Lischke,
  • Dorothee Schwinge,
  • Hans-Willi Mittrücker,
  • Ansgar W Lohse,
  • Annette Oxenius,
  • Christiane Wiegard,
  • Johannes Herkel

DOI
https://doi.org/10.1371/journal.pone.0086348
Journal volume & issue
Vol. 9, no. 1
p. e86348

Abstract

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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.