Liver-resident CD8+ T cells in viral hepatitis: not always good guys

Abstract

More than twenty years ago, non-HBV-specific CD8+ T cells were found to contribute to liver immunopathology in chronic HBV infection, while HBV-specific CD8+ T cells were noted to contribute to viral control. The role of HBV-specific CD8+ T cells in viral control and the mechanisms of their failure in persistent infection have been intensively studied during the last two decades, but the exact nature of nonspecific bystander CD8+ T cells that contribute to immunopathology has remained elusive. In this issue of the JCI, Nkongolo et al. report on their application of two methodological advances, liver sampling by fine-needle aspiration (FNA) and single-cell RNA sequencing (scRNA-Seq), to define a liver-resident CD8+ T cell population that was not virus specific but associated with liver damage, thus representing hepatotoxic bystander CD8+ T cells.

Figure 1. Cytotoxic and protective liver-resident memory CD8⁺ T cells define the intrahepatic immune landscape in chronic HBV infection.

(A) Hepatotoxic and protective liver-resident CD8⁺ T cells possess common properties, such as shared surface markers, as well as divergent properties, such as differing mechanisms of induction and effector functions. In protective liver-resident CD8⁺ T cells, secreted IL-2 participates in an autocrine feedback loop. Of note, hepatotoxic liver-resident CD8⁺ T cells are not HBV specific (bystander T cells), while protective liver-resident CD8⁺ T cells include a large proportion of HBV-specific CD8⁺ T cells. (B) Both T cell subsets are associated with viral load and inflammation in chronic infection. Notably, antiviral therapy can shift the dominance of the hepatotoxic population to the protective population.