CD8+ T Cell Control of Hepatitis B Virus Replication: Direct Comparison between Cytolytic and Noncytolytic Functions

Abstract

Resolution of hepatitis B virus (HBV) infection was believed to be attributed to the cytotoxic T cell–mediated killing of infected hepatocytes. However, studies in HBV transgenic mice and HBV-infected chimpanzees revealed that T cell control of HBV replication also involves cytokine-mediated noncytolytic mechanisms. The relative role of cytolytic and noncytolytic functions of virus-specific CD8+ T cells during interaction with HBV-producing hepatocytes is not well understood. By using HLA-A2 matched effector cells (CD8+ T cell line or clone) and target cells supporting full HBV replication, we demonstrate that virus-specific CD8+ T cells can inhibit HBV replication in HBV-producing hepatocytes with minimal cell lysis. Although CD8+ T cells kill a fraction of infected cells, this effect is minimal, and most of the viral inhibition is mediated by noncytolytic mechanisms. CD8+ T cells produce an array of cytokines, among which IFN-γ and TNF-α are responsible for HBV inactivation in the target cells. Blockade of IFN-γ and TNF-α abrogated the noncytolytic inhibition of HBV, indicating that these two cytokines mediate the control of HBV by noncytolytic mechanisms. Furthermore, treatment of the HBV-producing hepatocytes with rIFN-γ and rTNF-α resulted in an efficient suppression of viral replication without cytotoxicity. In contrast, coculture of the same target cells with activated HLA-mismatched mitogen-activated lymphomononuclear cells caused a marked cytolytic effect and was less effective in HBV control. These results provide direct evidence that virus-specific CD8+ T cells efficiently control HBV replication by noncytolytic mechanisms, and this effect is mediated by IFN-γ and TNF-α.

Importance of T Lymphocytes in Brain Injury, Immunodeficiency, and Recovery after Cerebral Ischemia

“…T C cells also produce pro-inflammatory cytokines, such as IFN-g and TNF, which serve to block viral replication as well as to promote the activation of other elements of the immune system (Phillips et al, 2010). Finally, 'unconventional' T lymphocytes that act to link the innate and adaptive immune systems (and are often called innate-like lymphocytes) include gd T cells (B5% of T cells; the only T cells that do not express CD3) and natural killer T (NKT) cells (Cerundolo and Kronenberg, 2010;D'Cruz et al, 2010).…”

MicroRNA-146a Feedback Suppresses T Cell Immune Function by Targeting Stat1 in Patients with Chronic Hepatitis B

“…Transfection of T cells with a miR-146a mimic resulted in a dramatic decrease of IFN-g, TNF-a, and IL-2 [the major cytokines that suppress HBV gene expression and replication (29)] at both the mRNA and protein levels, whereas a miR-146a inhibitor greatly promoted the expressions of these cytokines (Fig. 3A).…”

Hepatic CD206-positive macrophages express amphiregulin to promote the immunosuppressive activity of regulatory T cells in HBV infection

“…CD8 + CTLs eliminate infected cells [32]. It is considered that CD8 + T cells control HBV replication in a cytotoxic and noncytotoxic way through releasing cytotoxic mediators and antiviral cytokines, respectively [6]. However, adaptive immune response against HBV could be compromised or even fail, leading to persistent virus replication and spread.…”

“…The T cell response to HBV is vigorous, polyclonal, and multispecific in acutely infected patients who successfully clear the virus and relatively weak and narrowly focused in chronically infected patients, suggesting that clearance of HBV is T cell dependent [2]. HBV-specific CD8 + T cells clear viral infections by killing infected cells through physical contact with infected cells and by secretion of IFN-g and TNF-a to inhibit HBV gene expression and replication [3][4][5][6]. However, impaired immune response contributes to the failure of viral clearance.…”