Effective intrahepatic CD8+ T-cell immune responses are induced by low but not high numbers of antigen-expressing hepatocytes

Abstract

Liver infections with hepatotropic viruses, such as hepatitis B virus and hepatitis C virus are accompanied by viral persistence and immune failure. CD8+ T cells are crucial mediators of the intrahepatic antiviral immune response. Chronic infections of the liver and other organs correlate with T-cell exhaustion. It was previously suggested that high antigen load could result in T-cell exhaustion. We aimed at elucidating the impact of different intrahepatic antigen loads on the quality of CD8+ T-cell-mediated immunity by employing an infection-free transgenic mouse model expressing ovalbumin (Ova) as the target antigen. Adoptive transfer of OT-I cells induced a transient intrahepatic immune response toward both high and low Ova levels. However, antigen clearance was achieved only in mice expressing low antigen levels. In contrast, T cells exposed to high antigen levels underwent exhaustion and became depleted, causing antigen persistence. Moreover, when functional T cells were exposed to high intrahepatic antigen levels, a complete transition toward exhaustion was observed. Thus, this study shows that the antigen expression level in the liver correlates inversely with T-cell immunity in vivo and governs the efficiency of immune responses upon antigen presentation.

Efficacy of an Inhibitor of Hepatitis B Virus Expression in Combination With Entecavir and Interferon‐α in Woodchucks Chronically Infected With Woodchuck Hepatitis Virus

“…( 40,41 ) Furthermore, effective intrahepatic CD8+ T‐cell immune responses are only generated in mouse if the cells are exposed to hepatocytes expressing low levels of antigen. ( 5 ) In line with these concepts, a profound reduction of WHsAg levels in our study resulted in significant improvement of WHcAg‐ and WHsAg‐specific T‐cell responses. Further supporting this relationship, we also showed an inverse relationship between WHsAg levels and T‐cell responses from all the animals in our study, suggesting that a reduction in WHsAg improved the T‐cell response, as noted in the triple combination group (Fig.…”

“…In chronic HBV infection, continuous exposure to viral proteins, such as HBsAg in the periphery and liver, is thought to contribute to the exhaustion of antiviral cluster of differentiation (CD)8+ T cells. ( 4,5 ) Furthermore, several lines of evidence suggest that viral proteins influence virus‐specific immunity by directly modulating immune cells in both the innate and adaptive arms of the immune system. ( 6‐8 ) These studies are further supported by observations demonstrating that HBV interferes with innate antiviral immune responses in patients with chronic HBV infection.…”

Outcome of Antiviral Immunity in the Liver Is Shaped by the Level of Antigen Expressed in Infected Hepatocytes

“…This was only related to the different promoters driving the different expression levels of genes delivered through adenoviral vectors. Previously, high numbers of antigen‐expressing hepatocytes were claimed to cause CD8 T‐cell dysfunction, although only a range between 10% and 50% of antigen‐expressing hepatocytes were investigated . In a humanized murine model, the load of HBV antigens was determined to influence antiviral immunity .…”

“…Previously, high numbers of antigen-expressing hepatocytes were claimed to cause CD8 T-cell dysfunction, although only a range between 10% and 50% of antigen-expressing hepatocytes were investigated. (24,26,27) In a humanized murine model, the load of HBV antigens was determined to influence antiviral immunity. (28) However, in these mice the human liver graft and the human immune system were not human leukocyte antigen (HLA)matched, rendering it unlikely to detect HLA-specific T-cell responses.…”

A novel orally available small molecule that inhibits hepatitis B virus expression

“…Evidence suggests that in chronic HBV infection, high levels of dominant viral antigens such as HBsAg in the liver and periphery may contribute to exhaustion of antiviral CD8 + T-cells. [6][7][8][9] Furthermore, several reports describe HBsAg negatively regulating HBV-specific immune responses by direct modulation of dendritic cell, monocyte and natural killer cell functions. [10][11][12][13] Similarly, the most recent studies imply that HBV may interfere with antiviral innate immune responses in patients with CHB.…”