Dataset Information

CCL19 enhances CD8⁺ T-cell responses and accelerates HBV clearance.

ABSTRACT:

Background

Chemokine (C-C motif) ligand 19 (CCL19) is a leukocyte chemoattractant that plays a crucial role in cell trafficking and leukocyte activation. Dysfunctional CD8⁺ T cells play a crucial role in persistent HBV infection. However, whether HBV can be cleared by CCL19-activated immunity remains unclear.

Methods

We assessed the effects of CCL19 on the activation of PBMCs in patients with HBV infection. We also examined how CCL19 influences HBV clearance and modulates HBV-responsive T cells in a mouse model of chronic hepatitis B (CHB). In addition, C-C chemokine-receptor type 7 (CCR7) knockdown mice were used to elucidate the underlying mechanism of CCL19/CCR7 axis-induced immune activation.

Results

From in vitro experiments, we found that CCL19 enhanced the frequencies of Ag-responsive IFN-γ⁺ CD8⁺ T cells from patients by approximately twofold, while CCR7 knockdown (LV-shCCR7) and LY294002 partially suppressed IFN-γ secretion. In mice, CCL19 overexpression led to rapid clearance of intrahepatic HBV likely through increased intrahepatic CD8⁺ T-cell proportion, decreased frequency of PD-1⁺ CD8⁺ T cells in blood and compromised suppression of hepatic APCs, with lymphocytes producing a significantly high level of Ag-responsive TNF-α and IFN-γ from CD8⁺ T cells. In both CCL19 over expressing and CCR7 knockdown (AAV-shCCR7) CHB mice, the frequency of CD8⁺ T-cell activation-induced cell death (AICD) increased, and a high level of Ag-responsive TNF-α and low levels of CD8⁺ regulatory T (T_reg) cells were observed.

Conclusions

Findings in this study provide insights into how CCL19/CCR7 axis modulates the host immune system, which may promote the development of immunotherapeutic strategies for HBV treatment by overcoming T-cell tolerance.

SUBMITTER: Yan Y

PROVIDER: S-EPMC8316179 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Hepatitis B virus (HBV) persistently infected about 250 million people worldwide, and a curative treatment remains an unmet medical need. Among many approaches to treat chronic hepatitis B (CHB), therapeutic vaccines have been developed for two decades, but none have yielded promising results in clinical trials. Therefore, dissection of HBV clearance mechanisms during therapeutic vaccination in appropriate models, which could give rise to new curative therapies, is urgently needed. Growing evidence indicates that prolonged and intensive exposure of antigen-specific T cells to viral antigens is a major cause of T cell exhaustion, and decreases anti-HBV immunity efficacy of therapeutic vaccination. HBV X protein (HBx) is expressed at low levels, and the understanding of its immunogenicity and potential in therapeutic CHB vaccines is limited. METHODS:HBV genome sequences from CHB patients were cloned into a pAAV plasmid backbone and transfected into immunocompetent mouse hepatocytes through hydrodynamic injection. Mice carrying >?500?IU/mL serum HBV surface antigen (HBs) for more than 4?weeks were considered HBV carriers mimicking human CHB and received 3 doses of weekly HBx vaccine by subcutaneous immunization. Serum HBV clearance was evaluated by monitoring serum HBs and HBV-DNA titers. Residual HBV in the liver was evaluated by western blotting for HBV core antigen. The splenic antigen-specific T cell response was quantified by a 15-mer overlapping peptide-stimulated interferon-? enzyme-linked immunospot assay. Blood and hepatic immune cells were quantified by flow cytometric analysis. RESULTS:Our HBx-based vaccine induced systemic HBx-specific CD4+ and CD8+ T cell responses in HBV carrier mice and demonstrated significant HBs and HBV-DNA elimination. The protective effect persisted for at least 30?days without additional booster immunization. Different infiltrating myeloid cell subsets, each with distinctive roles during immune-mediated HBV clearance, were found in the liver of vaccinated mice. During vaccine therapy, inflammatory monocyte depletion resulted in sustained HBV clearance inhibition, whereas phagocytic monocyte-derived macrophage and Kupffer cell elimination resulted in only transient inhibition of vaccine-induced HBV clearance. CONCLUSIONS:We report the potential role of HBx as a major immunogen in an HBV therapeutic vaccine and the significance of a liver-infiltrating monocyte subset during hepatic viral clearance.

Dataset Information

CCL19 enhances CD8⁺ T-cell responses and accelerates HBV clearance.

Background

Methods

Results

Conclusions

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CCL19 enhances CD8⁺ T-cell responses and accelerates HBV clearance.