The role of natural killer cells and CD8(+) T cells in hepatitis B virus infection

Abstract

Hepatitis B virus (HBV) infection is one of the main causes of chronic liver diseases that may progress to liver cirrhosis and hepatocellular carcinoma. Host immune responses are important factors that determine whether HBV infection is cleared or persists. Natural killer (NK) cells represent the main effector population of the innate immune system and are abundant in the human liver. Recently, it has been demonstrated that NK cells not only exhibit antiviral functions but may also regulate adaptive immune responses by deletion of HBV-specific CD8(+) T cells. It is well-established that HBV-specific CD8(+) T cells contribute to virus elimination. However, the mechanisms contributing to CD8(+) T cell failure in chronic HBV infection are not well-understood. In this review, we will summarize the current knowledge about NK cells and CD8(+) T cells and illustrate their contribution to viral clearance and persistence in HBV infection. Moreover, novel immunological in vitro model systems and techniques to analyze HBV-specific CD8(+) T cells, which are barely detectable using current multimer staining methods, will be discussed.

Keywords: CD8+ T cells; T cell failure; functional dichotomy; hepatitis B virus; natural killer cells.

Figure 1

Natural killer cells as well as HBV-specific CD8⁺ T cells exhibit their antiviral functions by cytolytic (perforin and granzyme) and/or non-cytolytic (IFN-γ and TNF) mechanisms. However, CD8⁺ T cells express antigen-specific T cell receptors (TCRs) that interact with peptide-MHC I complexes on infected hepatocytes (H) whereas NK cell activation is thought to be antigen-independent. Effector functions and phenotype of both cell types are modulated during acute and chronic HBV infection. Indeed, different mechanisms play a role in regulating both effector populations, such as DCs, immunoregulatory cytokines (IL-10 and/or TGF-β) and expression of several inhibitory receptors. Furthermore, lack of CD4⁺ T cell help and interaction with regulatory T (Treg) cells may lead to CD8⁺ T cell dysfunction in chronically HBV-infected patients resulting in Bim-mediated apoptosis. Importantly, NK cells are also able to inhibit antiviral T cell responses by deleting HBV-specific CD8⁺ T cells in a TRAIL-dependent manner.