Abstract
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.
Highlights
Viral infections of the liver are a major cause of illness and death worldwide
Whereas wild-type mice had cleared the infection by day 15, the infection persisted in CIITA2/2 mice for at least 30 days
Numerical impairment of CD4+ T cells in acute Lymphocytic Choriomeningitis Virus (LCMV) infection seemed to prevent the clearance of LCMV-WE infection and to induce protracted viral hepatitis
Summary
Viral infections of the liver are a major cause of illness and death worldwide. In particular, virus-induced hepatitis, leading to chronic disease in hundreds of millions of people, is one of the most common causes of liver cirrhosis and liver cancer [1]. It is widely accepted that CD8+ T cells are the major effector cells that mediate viral clearance from the liver by removal of infected cells; the role of CD4+ T cells in viral hepatitis is less clear [6,7,8]. Relapse of HCV infection after initial control was associated with a loss of the antiviral CD4+ T-cell response [9]. Several studies (reviewed in [6]) indicate an association between a broad initial antiviral CD4+ T-cell response and viral clearance. On the other hand, depletion of CD4+ T cells in an early phase of HBV infection did not influence duration and outcome of acute HBV infection in a chimpanzee study [12]. The role of CD4+ T cells in the early phase of viral liver infection remains to be clarified
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