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

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. 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.

Restoration of type I interferon signaling in intrahepatically primed CD8+ T cells promotes functional differentiation

“…In summary, we have demonstrated that ISG expression is selectively suppressed in have been previously described (7,31). Over 98% of the splenic CD8 + T cells of COR93 TCR-Tg mice recognize a Kb-restricted epitope located between residues 93 and 100 in the HBcAg (MGLKFRQL), while approximately 83% of the splenic CD8 + T cells of ENV28 TCR-Tg mice recognize an Ld-restricted epitope located between residues 28 and 39 of the HBsAg (IPQSLDSWWTSL).…”

“…In all experiments, the HBV-Tg and B6 mice were matched for age (8–10 weeks), sex (male), and serum hepatitis B e antigen levels in HBV-Tg mice before experimental manipulation. COR93 TCR-Tg mice (lineage BC10.3, inbred CD45.1, H-2b) and ENV28 TCR-Tg mice (lineage 6C2.16, inbred Thy1.1 BALB/c, H-2d) have been previously described ( 7 , 31 ). Over 98% of the splenic CD8 + T cells of COR93 TCR-Tg mice recognize a Kb-restricted epitope located between residues 93 and 100 in the HBcAg (MGLKFRQL), while approximately 83% of the splenic CD8 + T cells of ENV28 TCR-Tg mice recognize an Ld-restricted epitope located between residues 28 and 39 of the HBsAg (IPQSLDSWWTSL).…”

Stem Cell-Derived Viral Antigen-Specific T Cells Suppress HBV Replication through Production of IFN-γ and TNF-⍺

“…HBV-specific CD8 + CTLs can mediate the killing of the infected hepatocytes and accelerate the clearance of cccDNA. Nevertheless, the HBV-specific CTLs can be deleted or dysfunctional or succumb to exhaustion in patients with chronic HBV infection ( Benechet and Iannacone, 2017 ; Kawashima et al., 2018 ). Moreover, recent studies showed that priming by hepatocytes, CD8 + T cells differentiated into dysfunctional HBV-specific CTLs, with partial overlap with those of exhausted or tolerant T cells; thus, these HBV-specific CTLs could not be rescued by treatment with immune checkpoint inhibitors such as anti-PD-L1 or CD40-mediated myeloid dendritic cells (mDCs)-activation ( Benechet et al., 2019 ; Isogawa et al., 2013 ).…”

An optimized protocol for the generation of HBV viral antigen-specific T lymphocytes from pluripotent stem cells

“…But after the adoptive cell transfer, the premature lymphocytes might change CD8 expression. Nevertheless, the HBV-specific CTLs can be deleted or dysfunctional or succumb to exhaustion in patients with chronic HBV infection ( Benechet and Iannacone, 2017 , Kawashima et al., 2018 ). Moreover, recent studies showed that priming by hepatocytes, CD8 + T cells differentiated into dysfunctional HBV-specific CTLs, with partial overlap with those of exhausted or tolerant T cells; thus, these HBV-specific CTLs could not be rescued by treatment with immune checkpoint inhibitors such as anti-PDL1 or CD40-mediated myeloid dendritic cells (mDCs)-activation ( Benechet et al., 2019 , Isogawa et al., 2013 ).…”