IL2-inducible T-cell Kinase is Required for HBV-induced Type T Interferon Expression and Antiviral Response

Background and Aims:Hepatitis B is a vaccine-preventable liver infection caused by the hepatitis B virus(HBV),and is seen as a serious global health problem.HBV infection induces the expression of type I interferon(IFN),including IFN-αand IFN-β,which have anti-HBV activities,and have been used for HBV treatment.IL2-inducible T-cell kinase(ITK)is a tyrosine kinase,which regulates T-cell differentiation and activation,while its precise effects on type I IFN production during HBV infection remain unknown.Methods:We monitored the ITK expression in peripheral blood mononuclear cells(PBMCs)from healthy donors and patients with acute and chronic HBV infection.We used ITK inhibitor ibrutinib to treat hepatocytes and evaluated the type I IFN expression after HBV infection.We also administrated ibrutinib to mice and evaluated its effect on HBV infection in vivo.We generated ITK,suppressor of cytokine signaling 1(SOCS1)knockout and ITK/SOCS1 double knockout cells using CRISPR,and monitored the HBV-induced type I IFN production.Results:ITK and type I IFN were upregulated in patients with acute HBV infection.Inhibition of ITK by ibrutinib suppressed HBVinduced expression of type I IFN mRNA in mice.ITK knockout cells had decreased IRF3 activation but promoted the expression of SOCS1.ITK negatively regulated SOSC1 expression.The down regulation of type I IFN in ITK knockout cells after HBV stimulation was abolished in the absence of SOCS1.Conclusions:ITK regulated HBV-induced expression of type I IFN mRNA by modulating SOCS1.