Pre-Activation of Toll-Like Receptor 2 Enhances CD8+ T-Cell Responses and Accelerates Hepatitis B Virus Clearance in the Mouse Models

Abstract

Toll-like receptors (TLRs) play a crucial role in activation of innate immunity, which is essential for inducing effective adaptive immune responses. Our previous studies have shown that toll-like receptor 2 (TLR2) is required to induce effective virus-specific T-cell responses against hepatitis B virus (HBV) in vivo. However, the contribution of TLR2 activation to adaptive immunity and HBV clearance remains to be clarified. In this study, we explored the hydrodynamic injection (HI) mouse models for HBV infection and examined how the TLR2 agonist Pam3CSK (P3C) influences HBV control and modulates HBV-specific T-cell response if applied in vivo. We found that TLR2 activation by P3C injection leads to the rapid but transient production of serum proinflammatory factors interleukin-6 and tumor necrosis factor-α and activation of CD8+ T cells in vivo. Then, the anti-HBV effect and HBV-specific T-cell immunity were investigated by TLR2 activation in the mouse models for persistent or acute HBV infections using HBV plasmids pAAV-HBV1.2 and pSM2, respectively. Both P3C application at early stage and pre-activation promoted HBV clearance, while only TLR2 pre-activation enhanced HBV-specific T-cell response in the liver. In the mouse model for acute HBV infection, P3C application had no significant effect on HBV clearance though P3C significantly enhanced the HBV-specific T-cell response. Collectively, TLR2 pre-activation enhances HBV-specific T-cell responses and accelerates HBV clearance in HI mouse models. Thus, the modulation of host immune status by TLR2 agonists may be explored for immunotherapeutic strategies to control HBV infection.

Diverse Virus and Host-Dependent Mechanisms Influence the Systemic and Intrahepatic Immune Responses in the Woodchuck Model of Hepatitis B

“…WHV infection modulated TLR-2 expression on PBMC and this reversely correlated with WHV DNA levels in woodchucks with AH and in animals with CH treated with ETV. In related study, TLR-2 agonists transiently enhanced production of IL-6 and TNFα, increased CD8+ T cell response, and augmented clearance of HBV in the hydrodynamic injection model of HBV infection (170).…”

Toll‐like receptor‐2/7‐mediated T cell activation: An innate potential to augment CD8+ T cell cytokine production

“…TLR2 knockout murine T cells show impaired clearance of Listeria monocytogenes in a T cell transfer infection model 64 . Furthermore, also CD8 + T cell responses against hepatitis B virus (HBV) were functionally impaired in TLR2 ‐/‐ mice, 111 and upon pretreatment with TLR2 ligands, HBV clearance was accelerated in mice 112 . This was attributed to elevated numbers of HBV‐specific T cells that exhibited enhanced IFN‐γ, TNF‐α and IL‐2 production 112 .…”

Hepatitis B Core Antigen Impairs the Polarization While Promoting the Production of Inflammatory Cytokines of M2 Macrophages via the TLR2 Pathway

“…Previous studies have indicated the inhibitory effects of hepatitis B surface antigen (HBsAg), e antigen (HBeAg), and HBV virions on the TLR-induced antiviral response which contributes to HBV persistence (41)(42)(43). Additionally, entecavir (ETV) treatment is thought to repair the expression and function of TLR2 in chronically woodchuck hepatitis virus (WHV)infected woodchucks (44), which was confirmed by a report showing that pre-activation of TLR2 can restore the CD8 + T cell response and promote HBV clearance (45).…”