Intrahepatic CD161hiCD8+T Cell Recruitment Has a Pathogenetic Potential in Chronic HBV Infection

Abstract

Backgrounds and aims: CD8+T cells are crucially associated with the fight against hepatitis B virus (HBV) infection. CD161 has been shown to express remarkably on HCV-specific CD8+T cells. However, the accurate function of CD161+CD8+T cells in HBV immunity or pathogenesis remains undetermined.

Methods: Blood samples were collected from 25 chronic hepatitis B (CHB) patients. Peripheral blood levels of CD161+CD8+T cells and their correlation with serum ALT levels were analyzed in CHB patients. To analyze the in vivo CD161+CD8+T cell's number, function, and intrahepatic recruitment characteristics, HBV replication mouse models were established. The expression of CD161 on HBV-specific CD8+T cells was also detected by analyzing CD161+CD8+T cell functions during infection.

Results: Patients with CHB infection had a markedly lower peripheral blood frequency of CD161+CD8+T cells than did healthy controls and negatively correlated with serum ALT level. Furthermore, compared to the control mice, the frequency of CD161+CD8+T cells was significantly decreased in the blood of acute and chronic HBV-replicating mice. Moreover, CHB-replicating mice had significantly increased hepatic levels of CD161+CD8+T cells, which was not observed in the acute group of mice. Additionally, the CD161+CD8+T cells were categorized into CD161^hi and CD161^intCD8+T cells and it was revealed that in the liver of CHB-replicating mice the primary recruited cells were CD161^hiCD8+T. Intrahepatic CD161^hiCD8+T cells demonstrated increased CXCR6 expression, enhanced production of cytokine IL-17 and TNF-ɑ, and reduced IFN-γ secretion. Accordingly, the CXCL16 mRNA expression in the liver tissue of CHB-replication mice was markedly higher than in acute HBV-replicating and control mice. The study also revealed that HBV-specific CD8+T cells were mainly CD161-CD8+T cells.

Conclusion: During HBV infection, the intrahepatic recruitment of CD161+CD8+T cells was mainly CD161^hiCD8+T cell subpopulation, which has a weak antiviral response, but increased pro-inflammatory effect, suggesting that CD161 may serve as a potential marker of liver-damaging T cells.

Keywords: CD161hiCD8+T cells; CXCL16; CXCR6; chronic HBV infection.