Immune tolerance prevents over-reactivity of the immune system to various environmental entities. However, it helps some pathogenic microbes avoid being eliminated and infect a host. Liver serves as an immune organ in human beings, and its immune response is delicately determined by the extent of inflammation. Nevertheless, liver's extrahepatic systemic tolerance mechanism during viral persistence is largely unknown. Moreover, the precise mediators controlling the induction or maintenance of liver-induced systemic tolerance are still in mystery.

Prof. TIAN Zhigang's team at University of Science & Technology of China of Chinese Academy of Sciences identified the underlying mechanism of hepatitis B virus (HBV) immune tolerance. The study entitled “Interferon-γ facilitates hepatic antiviral T cell retention for the maintenance of liver-induced systemic tolerance” was published online in JEM.

The researchers observed that the classical immune effector molecule interferon-γ (IFN-γ) made HBV specific immune effector cells, which were supposed to circulate in the whole body, stay in liver for a long time. Then the cells are removed, resulting in “Graveyard effect”. This process was observed in a well-established mouse model of HBV persistence–induced systemic tolerance. It demonstrated the liver’s entire and negative control over general immune system, as a partial organ.

They found that IFN-γ deficiency made liver lose tolerance and then respond to vaccination. The anti-HBV responses recovered because CD4+ T cells retained rather than that inhibitory cells should decrease. Further study showed that HBV core antigen induced hepatic CD4+ T produces IFN-γ continuously, and IFN-γ promoted liver-resident macrophages to yield CXCL9, T cells chemokine receptor. IFN-γ also facilitated antiviral CD4+ T cells to retain in the liver to apoptosis in a CXCR3-dependent manner. Thus anti-HBV T cells in the whole body were “clonal eliminated” by hepatic immune tolerance mechanism.

The findings show how HBV immune tolerance goes and are important to develop future HBV therapeutic vaccines.

The research was supported by the National Science and Technology Major Project of the Ministry of Science and Technology of China, the National Major Research Program of China, the National Natural Science Foundation of China, and the Key Program of the Chinese Academy of Sciences.