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

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.

Apoptosis; CD8+ T cell; Chemokine (C–C motif) ligand 19 (CCL19); Hepatitis B virus; Regulatory T cell (Treg cell).