Intrahepatic Cross-Presentation and Hepatocellular Antigen Presentation Play Distinct Roles in the Induction of Hepatitis B Virus-Specific CD8+T Cell Responses

ABSTRACTCD8+T cells are the key cellular effectors mediating the clearance of hepatitis B virus (HBV) infections. However, early immunological events surrounding the priming of HBV-specific CD8+T cell responses remain poorly understood. This study examined the importance of priming location and the relative contribution of endogenous antigen presentation by hepatocytes versus cross-presentation by bone marrow-derived cells to the induction of functional HBV-specific CD8+T cell responses using the animal models of acute and chronic HBV infection. Functional HBV-specific CD8+T cell responses could be induced to intrahepatically expressed HBV even when T cell homing to the lymphoid tissues was severely suppressed, suggesting that functional priming could occur in the liver. The expansion of HBV-specific CD8+T cells was significantly reduced in the mice whose major histocompatibility complex (MHC) class I expression was mostly restricted to nonhematopoietic cells, suggesting the importance of cross-presentation by hematopoietic cells in the induction of HBV-specific CD8+T cells. Strikingly, the expansion and cytolytic differentiation of HBV-specific CD8+T cells were reduced even more severely in the mice whose MHC class I expression was restricted to hematopoietic cells. Collectively, these results indicate that cross-presentation is required but relatively inefficient in terms of inducing the cytolytic differentiation of HBV-specific CD8+T cells by itself. Instead, the expansion and functional differentiation of HBV-specific CD8+T cells are primarily dependent on hepatocellular antigen presentation.IMPORTANCEHepatitis B virus (HBV) causes acute and chronic hepatitis. Approximately 260 million people are chronically infected with HBV and under an increased risk of developing cirrhosis and hepatocellular carcinoma. Host immune responses, particularly HBV-specific CD8+T cell responses, largely determine the outcome of HBV infection. It is widely accepted that antigen inexperienced CD8+T cells should be initially activated by professional antigen-presenting cells (pAPCs) in lymphoid tissues to differentiate into effector CD8+T cells. However, this notion has not been tested for HBV-specific CD8+T cells. In this study, we show that HBV-specific CD8+T cell responses can be induced in the liver. Surprisingly, antigen presentation by hepatocytes is more important than cross-presentation by hematopoietic cells for the induction of HBV-specific CD8+T cell responses. These results revealed a previously unappreciated role of antigen presentation by hepatocytes in the induction of HBV-specific CD8+T cell responses.

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Type I Interferon Signaling Prevents Hepatitis B Virus-Specific T Cell Responses by Reducing Antigen Expression

Journal of Virology ◽

10.1128/jvi.01099-18 ◽

2018 ◽

Vol 92 (23) ◽

Cited By ~ 1

Author(s):

Keigo Kawashima ◽

Masanori Isogawa ◽

Susumu Hamada-Tsutsumi ◽

Ian Baudi ◽

Satoru Saito ◽

...

Keyword(s):

Hepatitis B Virus ◽

T Cell ◽

Hepatitis B ◽

Type I Interferon ◽

T Cell Responses ◽

Antigen Expression ◽

Type I ◽

Interferon Signaling ◽

Cell Responses ◽

B Virus

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_IND [Aa], C_JPN22 [C22], and D_IND60 [D60]) that express various amounts of HBV antigens into the livers of C57BL/6 (B6) (H-2b) mice and B10.D2 (H-2d) mice. 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 H-2d mice. 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–/–) (H-2b) mice. 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 small interfering RNA (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 contributions 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 rates between HBV clones after hydrodynamic transduction were 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 the HBV-specific CD8+ T cell response is regulated primarily by the initial antigen expression level.

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