PD1/PDL1and CD28/CD80Pathways Modulate Natural Killer T Cell Function To Inhibit Hepatitis B Virus Replication

The α-galactosylceramide (α-GalCer)-activated NKT cells haveanti-viral properties against hepatitis B virus (HBV). However,α-GalCer-activation of the natural killer T (NKT) cells can induce anergy.We hypothesized that this effect may be overcome by a treatment strategythat includes manipulation of the CD28/CD80co-stimulatory andPD1/PDL1co-inhibitory signals of NKT cells, thereby enhancing theanti-HBV effect of α-GalCer. To this end, we established a transgenicmouse model of chronic HBV infection and investigated the hepatic NKTcell frequencies, functions, and expression of immuno-modulatory factors.Results demonstrated that, compared with uninfected control mice, thehepatic NKT cells from HBV-transgenic mice displayed lower frequencies,impaired capabilities to produce interferon (IFN)-γ and interleukin (IL)-4,higher expression of PD1, and lower expression of CD28. However, whenthe hepatic mononuclear cells (MNCs) were isolated from theHBV-transgenic mice, α-GalCer exposure in culture remarkablyup-regulated both PD1+NKT and CD28+NKTcells. Furthermore, whenHBV-transgenic mice were treated with combination therapies consisting of α-GalCer and anti-PDL1monoclonal antibody (mAb) and/oranti-CD80/anti-CD28mAbs, IFN-γ+NKT cell frequency was selectivelyincreased and HBV replication was suppressed; however, these effects wereaccompanied by varying degrees and types of liver damage. The α-GalCertherapy with CD28/CD80signal activation produced not only the mostrobust suppression of HBV replication but also the least extensive and mosttransient liver injury. In conclusion, α-GalCer combination therapy thatmodulates the CD28/CD80pathways of NKT cells may represent apromising approach to inhibit HBV replication in chronically infectedindividuals...