Spatiotemporal Differences in Presentation of CD8 T Cell Epitopes during Hepatitis B Virus Infection

Khakpoor, Atefeh; Ni, Yi; Chen, L.-W. Antony; Ho, Zi Zong; Oei, Vincent Yi Sheng; Yang, Ninghan; Giri, Reshmi; Chow, Jia Xin; Tan, Anthony T.; Kennedy, Patrick T.; Maini, Mala K.; Urban, Stephan; Bertoletti, Antonio

doi:10.1128/jvi.01457-18

Cited by 30 publications

(26 citation statements)

References 41 publications

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“…In this study, we hypothesized that, in HBV-infected hepatocytes, the ethanol metabolite Ach suppresses the HBV peptide-MHC class I complexes (CTL epitopes) presentation on hepatocyte surface, which may potentially decrease the clearance of HBV-expressing cells. As shown by others (36), positive immunofluorescent staining with HLA-A2-HBV core 18 -27 antibody was found in three of eight liver biopsy samples obtained from CHB patients (36). The same study demonstrated that not viral replication but viral protein synthesis is related to efficient peptide-HLA-A2 complex presentation on hepatocyte surface.…”

Section: Discussionsupporting

confidence: 58%

“…To mimic ethanol metabolism in stably HBV-transfected ethanol nonmetabolizing HepG2.2.15 cells, which express HBV core peptide 18 -27 in the context of HLA-A2 (36), we employed an acetaldehyde (Ach)-generating system (AGS) (19 -22) providing a continuous enzymatic generation of physiologically relevant amounts of Ach without causing necrotic cell death (22). Since liver contains mixed proteasomes (constitutive and IPRs), the most efficient generation of antigenic peptides requires hepatocyte exposure to IFN␥ (36,60). Thus, HBV-transfected cells were exposed to IFN␥ for activation of IPR/peptide cleavage/trafficking of peptide complex to the cell surface.…”

Section: Introductionmentioning

confidence: 99%

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Acetaldehyde suppresses the display of HBV-MHC class I complexes on HBV-expressing hepatocytes

Ganesan

Krutik

Makarov

et al. 2019

American Journal of Physiology-Gastrointestinal and Liver Physi

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Hepatitis B virus (HBV) infection and alcoholism are major public health problems worldwide, contributing to the development of end-stage liver disease. Alcohol intake affects HBV infection pathogenesis and treatment outcomes. HBV-specific cytotoxic T lymphocytes (CTLs) play an important role in HBV clearance. Many previous studies have focused on alcohol-induced impairments of the immune response. However, it is not clear whether alcohol alters the presentation of HBV peptide-major histocompatibility complex (MHC) class I complexes on infected hepatocytes resulting in escape of its recognition by CTLs. Hence, the focus of this study was to investigate the mechanisms by which ethanol metabolism affects the presentation of CTL epitope on HBV-infected hepatocytes. As demonstrated here, although continuous cell exposure to acetaldehyde-generating system (AGS) increased HBV load in HepG2.2.15 cells, it decreased the expression of HBV core peptide 18–27-human leukocyte antigen-A2complex (CTL epitope) on the cell surface. Moreover, we observed AGS-induced suppression of chymotrypsin- and trypsin-like proteasome activities necessary for peptide processing by proteasome as well as a decline in IFNγ-stimulated immunoproteasome (IPR) function and expression of PA28 activator and immunoproteasome subunits LMP7 and LMP2. Furthermore, IFNγ-induced activation of peptide-loading complex (PLC) components, such as transporter associated with antigen processing (TAP1) and tapasin, were suppressed by AGS. The attenuation of IPR and PLC activation was attributed to AGS-triggered impairment of IFNγ signaling in HepG2.2.15 cells. Collectively, all these downstream events reduced the display of HBV peptide-MHC class I complexes on the hepatocyte surface, which may suppress CTL activation and the recognition of CTL epitopes on HBV-expressing hepatocytes by immune cells, thereby leading to persistence of liver inflammation. NEW & NOTEWORTHY Our study shows that in HBV-expressing HepG2.2.15 cells, acetaldehyde alters HBV peptide processing by suppressing chymotrypsin- and trypsin-like proteasome activities and decreases IFNγ-stimulated immunoproteasome function and expression of PA28 activator and immunoproteasome subunits. It also suppresses IFNγ-induced activation of peptide-loading complex (PLC) components due to impairment of IFNγ signaling via the JAK-STAT1 pathway. These acetaldehyde-induced dysfunctions reduced the display of HBV peptide-MHC class I complexes on the hepatocyte surface, thereby leading to persistence of HBV infection.

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Section: Discussionsupporting

confidence: 58%

Section: Introductionmentioning

confidence: 99%

Acetaldehyde suppresses the display of HBV-MHC class I complexes on HBV-expressing hepatocytes

Ganesan

Krutik

Makarov

et al. 2019

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…The clearance of intracellular pathogens by the immune response is widely believed to be mediated primarily by the destruction of infected cells by major histocompatibility complex (MHC) class-I restricted CD8 + T cells. Upon Ag recognition, CTLs can secrete potent antiviral cytokines such as IFN-γ and TNF-α, which can effectively eliminate viral infection without killing the infected cells ( Khakpoor et al., 2019 ). To evaluate the extent to which the antiviral effects reduce HBV replication, we examined the production of the antiviral cytokines IFN-γ and TNF-α from the intra-hepatic lymphocytes of mice receiving HBV viral Ag-specific or OVA-specific iPSC-CTLs.…”

Section: Resultsmentioning

confidence: 99%

“…The clearance of intracellular pathogens by the immune response is widely thought to be mediated primarily through the destruction of the infected cells by MHC class I-restricted CD8 + CTLs. Upon Ag recognition, CTLs can also secrete potent antiviral cytokines such as IFN-γ and TNF-α ( Khakpoor et al., 2019 ; Zeng et al., 2016 ; Xia et al., 2016 ; Park et al., 2016 ), which can eradicate viral infections without killing the infected cells. Thus, we examined the productions of antiviral cytokines in the liver and revealed that HBV viral Ag-specific iPSC-CTLs-induced reduction of HBV replication was mediated by IFN-γ and TNF-α.…”

Section: Discussionmentioning

confidence: 99%

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

Haque¹,

Lei²,

Xiong³

et al. 2020

iScience

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Summary The viral antigen (Ag)-specific CD8 + cytotoxic T lymphocytes (CTLs) derived from pluripotent stem cells (PSCs), i.e., PSC-CTLs, have the ability to suppress hepatitis B virus (HBV) infection. After adoptive transfer, PSC-CTLs can infiltrate into the liver to suppress HBV replication. Nevertheless, the mechanisms by which the viral Ag-specific PSC-CTLs provoke the antiviral response remain to be fully elucidated. In this study, we generated the functional HBV surface Ag-specific CTLs from the induced PSC (iPSCs), i.e., iPSC-CTLs, and investigated the underlying mechanisms of the CTL-mediated antiviral replication in a murine model. We show that adoptive transfer of HBV surface Ag-specific iPSC-CTLs greatly suppressed HBV replication and prevented HBV surface Ag expression. We further demonstrate that the adoptive transfer significantly increased T cell accumulation and production of antiviral cytokines. These results indicate that stem cell-derived viral Ag-specific CTLs can robustly accumulate in the liver and suppress HBV replication through producing antiviral cytokines.

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“…A recent study showed that HBV antigen presentation is also heterogeneous within an HBV-infected liver. Indeed, HBV-infected hepatocytes expressed antigens in different quantities and localizations and from different sources resulting in a non-uniformal HLA class I/HBV epitope presentation in the liver and thereby triggering different level of HBV-specific CD8 + T-cell activation (54). Moreover, antigens produced and secreted in high quantities by HBV-infected hepatocytes such as HBc antigen may be presented either by hepatocytes themselves or cross-presented by other professional antigen-presenting cells (55).…”

Section: Heterogeneity Of Exhausted Hbv-specific Cd8+ T Cellsmentioning

confidence: 99%

Heterogeneity of HBV-Specific CD8+ T-Cell Failure: Implications for Immunotherapy

2019

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Chronic hepatitis B virus (HBV) infection is a major global health burden affecting around 257 million people worldwide. The consequences of chronic HBV infection include progressive liver damage, liver cirrhosis, and hepatocellular carcinoma. Although current direct antiviral therapies successfully lead to suppression of viral replication and deceleration of liver cirrhosis progression, these treatments are rarely curative and patients often require a life-long therapy. Based on the ability of the immune system to control HBV infection in at least a subset of patients, immunotherapeutic approaches are promising treatment options to achieve HBV cure. In particular, T cell-based therapies are of special interest since CD8+ T cells are not only capable to control HBV infection but also to eliminate HBV-infected cells. However, recent data show that the molecular mechanisms underlying CD8+ T-cell failure in chronic HBV infection depend on the targeted antigen and thus different strategies to improve the HBV-specific CD8+ T-cell response are required. Here, we review the current knowledge about the heterogeneity of impaired HBV-specific T-cell populations and the potential consequences for T cell-based immunotherapeutic approaches in HBV cure.

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Spatiotemporal Differences in Presentation of CD8 T Cell Epitopes during Hepatitis B Virus Infection

Cited by 30 publications

References 41 publications

Acetaldehyde suppresses the display of HBV-MHC class I complexes on HBV-expressing hepatocytes

Acetaldehyde suppresses the display of HBV-MHC class I complexes on HBV-expressing hepatocytes

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

Heterogeneity of HBV-Specific CD8+ T-Cell Failure: Implications for Immunotherapy

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