LAUSR

Patients with chronic hepatitis B virus (HBV) infection are at risk of superinfection with the Hepatitis D virus (HDV), a small circular RNA virus that uses the HBV surface antigen (HBsAg) to envelope its genome and infect hepatocytes. Superinfection with HDV increases the severity of viral hepatitis, accelerates the progression to cirrhosis and increases the risk of developing hepatocellular carcinoma. This process is thought to be immune-mediated, but the factors that drive disease pathogenesis are not well understood. Tools to study the role of CD8 T cells in chronic HDV infection only recently became available when a comprehensive set of CD8 T cell epitopes was identified in 3 independent publications. These studies also revealed the presence of HDV mutations in both individual patients and at the population level. HDV mutations were associated with a memory-like phenotype of the corresponding CD8 T cells, consistent with the notion that stimulation via their HDV-specific T cell receptor (TCR) had ceased. These findings imply that alternative mechanisms of immune cell activation may contribute to liver disease pathogenesis. Indeed, HDV but not HBV results in vigorous innate immune responses such as interferon (IFN)-b and IFN-k-mediated induction of interferon-stimulated genes. Innate immune cells with constitutively high expression of receptors for IFN-a/b and/or other inflammatory cytokines such as IL-12 and IL-18 constitute a large part of the intrahepatic infiltrate, even in the healthy liver. Of particular interest are mucosalassociated invariant T (MAIT) cells which comprise up to 40% of the intrahepatic immune cell population, even in the healthy liver. MAIT cells are innate-like T cells, typically identified by their expression of the C-type lectin CD161 and a semi-invariant TCR with conserved Va7.2 chain. They are stimulated in a TCRdependent manner by bacterial metabolites that are presented by the non-classical, monomorphic major histocompatibility