Pathogenic CD8 T cells defined by longitudinal liver sampling in chronic hepatitis B patients starting antiviral therapy

Abstract

SummaryAccumulation of activated immune cells results in non-specific hepatocyte killing in chronic hepatitis B (CHB), leading to fibrosis and cirrhosis. We enrolled 15 CHB patients with active liver damage to receive antiviral therapy, and performed longitudinal liver sampling using fine-needle aspiration to investigate mechanisms of CHB pathogenesis in the human liver. Single-cell sequencing of total liver cells revealed a distinct liver-resident, polyclonal CD8 T cell population that was enriched at baseline and displayed a highly activated immune signature during liver damage. Cytokine combinations, identified by in silico prediction of ligand-receptor interaction, induced the activated phenotype in healthy liver CD8 T cells, resulting in non-specific Fas ligand-mediated killing of target cells. These results define a CD8 T cell population in the human liver that can drive pathogenesis, and a key pathway involved in their function in CHB patients.

Intrahepatic T cells with NK-like properties: Expanding the repertoire of lymphocytes sensitive to bystander activation

“…10 However, IL-2 can coordinate with IL-12 to induce the activation of a large hepatotoxic CD8 + T cell population that can non-specifically kill hepatocytes through a Fas ligand-dependent mechanism. 11,12 Similarly, hepatotoxic antigen non-specific CD8+ T cell populations that contribute to inflammation and disease stage have been observed in Hepatitis Delta virus infection. 13 While the HBV-related liver disease samples included in the study by Koh et al originated from end-stage disease, they support the role of TCR-independent bystander T cell activation in progression of liver disease.…”