Interleukin 27 (IL-27) productions in the liver microenvironment confer an immunosuppressive role and enhance hepatitis B viral persistence

Abstract

Background: Persistent chronic hepatitis B virus (HBV) infection leads to chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. The immunosuppressive tissue microenvironment in the liver restricts the immune response, potentially facilitating persistent HBV infection. This study examined the expression of immunity-related factors in the liver in response to HBV.

Methods: We performed gene expression profiling on mice subjected to HBV DNA hydrodynamic transfection to identify transcriptomic changes. The expression of IL-27 was validated through Western blotting, ELISA, and immunohistochemical staining. Liver macrophages in mice were depleted using clodronate-liposomes to evaluate their role in IL-27 production. IL-27 knockout mice were generated to examine the effects of IL-27 deficiency on CD8 T cell dysfunction and HBV persistence.

Results: Transcriptomic analysis demonstrated that IL-27 is significantly induced in the liver in response to HBV DNA. The elevated levels of IL-27 are strongly correlated with HBV persistence and are linked to CD8 T cell dysfunction, characterized by increased expression of PD-1 and Tim-3, along with reduced IFN-γ production in liver-infiltrating T cells. Furthermore, depleting macrophage-lineage cells using clodronate-liposomes significantly reduces IL-27 production in the liver and promotes viral clearance. Additionally, mice with IL-27 deficiency exhibit enhanced HBV clearance and restored CD8 T cell function.

Conclusions: Collectively, IL-27 is significantly induced by HBV in the liver, and its production is strongly associated with HBV persistence and CD8 T cell dysfunction. This highlights the immunosuppressive role of IL-27 in the liver microenvironment and suggests that IL-27 could serve as a potential therapeutic target for HBV infection.

Keywords: CD8 T cell dysfunction; HBV persistence; IL-27; Liver microenvironment.