Circulating CD8 T cells are sentinels for intrahepatic T cell responses during HBV infection

Chronic hepatitis B (CHB) is characterized by scarcity and dysfunction of virus-specific CD8 T-cells, for which immune-therapies, such as the therapeutic vaccination TherVacB, aim to generate virus-specific T-cells to control infection. This study sought to identify whether circulating HBV-specific CD8 T-cells reflect the intrahepatic T-cell response against infected hepatocytes and to identify biomarkers on circulating HBV-specific CD8 T-cells that predict immune control.

Using pre-clinical models of HBV as well as patient samples during an acute-resolving or chronic infection, we studied the dynamics of virus-specific T-cell response by flow cytometry and single-cell RNA sequencing.

Single-cell transcriptomic and protein-level analysis detected the generation of CD8 T-cells in the liver which were characterized by expression of CXCR6 and, during acute-resolving infection, were potent effector cells, whereas CD8 T-cells during persistent infection were dysfunctional and showed a CREM signature. Strikingly, scRNAseq analysis revealed close similarity between circulating and intrahepatic HBV-specific CD8 T-cells. We defined signatures that discriminate between lymphoid-tissue derived HBV-specific CD8 T-cells compared to HBV-specific CD8 T-cells, which had seen their antigen in the liver, thereby enabling the evaluation of intrahepatic HBV-specific CD8 T-cell responses in peripheral blood. Notably, the ability to predict T-cell immunity in infected organs was restricted to hepatotropic infections, as circulating CD8 T-cells did not reflect the T-cell response in the lung following influenza A virus infection. Importantly, we confirmed the presence of the immune signatures (termed “liver immunity index”) that predict immune control in HBV-specific CD8 T-cells from patients with acute as compared to chronic hepatitis B.

Publication History

Article published online:
20 January 2025