J Virol. 2018 Sep 12. pii: JVI.01099-18. doi: 10.1128/JVI.01099-18. [Epub ahead of print]
Type I interferon signaling prevents hepatitis B virus-specific T cell responses by reducing antigen expression.
Kawashima K1,2, Isogawa M3, Hamada-Tsutsumi S2, Baudi I2, Saito S1, Nakajima A1, Tanaka Y3.
Author information
1
Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine, Yokohama, Japan.
2
Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
3
Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan [email protected][email protected].
Abstract
Robust virus-specific CD8+ T cell responses are required for the clearance of hepatitis B virus (HBV). However, the factors that determine the magnitude of HBV-specific CD8+ T cell responses are poorly understood. To examine the impact of genetic variations of HBV on HBV-specific CD8+ T cell responses, we introduced three HBV clones (Aa, C22, D60) that express varying amounts of HBV antigens into the livers of C57BL/6 (B6) mice (H-2b) and B10.D2 mice (H-2d). In B6 mice, clone C22 barely induced HBV-specific CD8+ T cell responses and persisted the longest, while clone D60 elicited strong HBV-specific CD8+ T cell responses and was rapidly cleared. These differences between HBV clones largely diminished in B10.D2 mice (H-2d). Interestingly, the magnitude of HBV-specific CD8+ T cell responses in B6 mice was associated with the HB core antigen expression level during the early phase of HBV transduction. Surprisingly, robust HBV-specific CD8+ T cell responses to clone C22 were induced in interferon-α/β receptor-deficient (IFN-αβR-/-) mice (H-2b). The induction of HBV-specific CD8+ T cell responses to C22 in IFN-αβR-/- mice reflects enhanced HBV antigen expression because the suppression of antigen expression by HBV-specific siRNA attenuated HBV-specific T cell responses in IFN-αβR-/- mice and prolonged HBV expression. Collectively, these results suggest that HBV genetic variation and type I interferon signaling determine the magnitude of HBV-specific CD8+ T cell responses by regulating the initial antigen expression levels.IMPORTANCE Hepatitis B virus (HBV) causes acute and chronic infection, and approximately 240 million people are chronically infected with HBV worldwide. It is generally believed that virus-specific CD8+ T cell responses are required for the clearance of HBV. However, the relative contribution of genetic variation and innate immune responses to the induction of HBV-specific CD8+ T cell responses are not fully understood. In this study, we discovered that different clearance rate between HBV clones after hydrodynamic transduction was associated with the magnitude of HBV-specific CD8+ T cell responses and initial HB core antigen expression. Surprisingly, type I interferon signaling negatively regulated HBV-specific CD8+ T cell responses by reducing early HBV antigen expression. These results show that the magnitude of HBV-specific CD8+ T cell response is primarily regulated by the initial antigen expression level.