Balance lost: T cell immunity in progressive HBV infection.

Abstract

An efficient, coordinated immune response is key to the resolution of viral infections. Indeed, the spontaneous elimination of hepatitis B virus (HBV) during acute infection is associated with the emergence of functionally competent antiviral CD8? and CD4? T cell responses [1]. In contrast, chronic infection is characterized by the presence of dysfunctional HBV-specific CD8? T cells that are unable to control viral infection [2, 3]. Since current antiviral therapies are able to cure only a small number of patients, the restoration of antiviral HBV-specific CD8? T cells is a promising goal for novel therapeutic strategies. It is likely that several factors contribute to CD8? T cell dysfunction in chronic HBV infection, including the action of regulatory T cells (Tregs), depletion of arginine in the inflamed liver microenvironment causing reduced T cell receptor signalling, release of immunoregulatory cytokines, enhanced T cell apoptosis, exposure to high loads of viral antigen, and the tolerogenic liver environment [2–4]. Moreover, several reports have described the up-regulation of inhibitory receptor expression by HBV-specific CD8? T cells [5–12]. These studies suggest that HBV-specific CD8? T cells are in a state of T cell exhaustion. Exhausted T cells are characterized by poor effector functions, expression of inhibitory receptors, and a distinct ‘‘exhaustive’’ differentiation and transcriptional state [13]. In addition to HBV-specific CD8? T cells, CD4? T cells play an important role in chronic HBV infection. Indeed, several reports have reported an up-regulation of Tregs in chronic HBV infection [14–17] that were able to impair HBV-specific CD8? T cell function. Tregs play a crucial role in the immune system by preventing excessive inflammatory T cell responses and limiting immunopathology. However, the regulatory function of regulatory T cells may be counteracted by proinflammatory T cell responses. In particular, IL-17-producing CD4? T cells (TH17 cells) are critically involved in the induction and maintenance of inflammation and are enriched in inflammatory diseases. TH17 cells are able to secrete several potentially proinflammatory cytokines depending on STAT3 signaling, including IL-17, IL-22, GM-CSF, and TNF that modulate the tissue response during inflammation [18, 19]. Of note, the frequency of TH17 cells increases with disease progression in chronic HBV infection. Indeed, an enrichment of circulating and intrahepatic TH17 cells is observed in liver inflammation and correlates with elevated liver enzymes and histological activity index [20]. Thus, a picture emerges in which Tregs may contribute to immune tolerance in chronic HBV infection by limiting HBV-specific CD8? T cell function resulting in T cell exhaustion, but this effect may be overcome by TH17 cells, causing immunopathology. The mechanisms that are responsible for maintaining the balance of Tregs and TH17 cells are currently unclear. However, it seems reasonable to speculate that a dysregulated cellular immune balance is responsible for the different immunological stages of chronic HBV infection (e.g., immune tolerance phase with high viral replication in the absence of liver damage, and immune activation phase with significant liver inflammation and reduced viral replication and phases of relative immune control with low viral replication and low liver inflammation). Moreover, it is thought that the dysregulation of the antiviral response with a shift to proinflammatory T cell responses may lead to chronic hepatic inflammation resulting in progressive liver disease, liver cirrhosis, and hepatocellular carcinoma (Fig. 1). B. Bengsch R. Thimme (&) Department of Medicine II, University Hospital of Freiburg, Freiburg, Germany e-mail: robert.thimme@uniklinik-freiburg.de