PD-1/PDL1 and CD28/CD80 pathways modulate natural killer T cell function to inhibit hepatitis B virus replication

Area of Science:

• Immunology
• Hepatology
• Virology

Background:

• Natural killer T (NKT) cells activated by α-Galactosylceramide (α-GalCer) exhibit antiviral properties against hepatitis B virus (HBV).
• α-GalCer activation can lead to NKT cell anergy, potentially limiting its therapeutic efficacy.
• Chronic HBV infection impairs hepatic NKT cell function and alters immune checkpoint molecule expression.

Purpose of the Study:

• To investigate whether modulating CD28/CD80 costimulatory and PD-1/PDL1 coinhibitory signals can overcome α-GalCer-induced NKT cell anergy.
• To evaluate the therapeutic potential of combination therapies involving α-GalCer and immune checkpoint modulators in a mouse model of chronic HBV infection.

Main Methods:

• Establishment of a transgenic mouse model for chronic HBV infection.
• Analysis of hepatic NKT cell frequencies, cytokine production (IFN-γ, IL-4), and expression of PD-1 and CD28.
• Treatment of HBV transgenic mice with α-GalCer, anti-PDL1 monoclonal antibody (mAb), and/or anti-CD80/anti-CD28 mAbs.

Main Results:

• HBV transgenic mice showed reduced NKT cell frequency, impaired IFN-γ and IL-4 production, and altered PD-1 and CD28 expression compared to controls.
• α-GalCer treatment upregulated PD-1 and CD28 on NKT cells in vitro.
• Combination therapies selectively increased IFN-γ(+) NKT cells and suppressed HBV replication, with varying degrees of liver damage.
• Activating CD28/CD80 signals was more effective and caused less liver injury than blocking PD-1/PDL1 signals.

Conclusions:

• Modulating CD28/CD80 costimulatory pathways in conjunction with α-GalCer offers a promising strategy to inhibit HBV replication.
• Targeting CD28/CD80 costimulation appears more beneficial than PD-1/PDL1 blockade for enhancing anti-HBV NKT cell responses.
• This approach holds potential for treating chronic HBV infection by revitalizing NKT cell function.