MMP2/MMP9-mediated CD100 shedding is crucial for inducing intrahepatic anti-HBV CD8 T cell responses and HBV clearance

Abstract Background & Aims CD100 is constitutively expressed on T cells and can be cleaved from the cell surface by matrix metalloproteases (MMPs) to become soluble CD100 (sCD100). Both membrane-bound CD100 (mCD100) and sCD100 play important immune regulatory functions that promote immune cell activation and responses. The aim of this study was to investigate the expression and role of mCD100 and sCD100 in regulating antiviral immune responses during HBV infection. Methods mCD100 expression on T cells, sCD100 levels in the serum and MMP expression in the liver and serum were analyzed in patients with chronic hepatitis B (CHB) and HBV replicating mice. The ability of sCD100 in mediating antigen-presenting cell maturation, HBV-specific T cell activation and HBV clearance were analyzed in HBV replicating mice and CHB patients. Results CHB patients had higher mCD100 expression on T cells and lower serum sCD100 levels than healthy controls. Therapeutic sCD100 treatment resulted in the activation of dendritic cells and liver sinusoidal endothelial cells, enhanced HBV-specific CD8 T cell response and accelerated HBV clearance, while blockade of its receptor CD72 attenuated the intrahepatic anti-HBV CD8 T cell response. Together with MMP9, MMP2 mediated mCD100 shedding from the T cell surface. CHB patients had significantly lower serum MMP2 levels, which positively correlated with serum sCD100 levels. Inhibition of MMP2/9 activity resulted in an attenuated anti-HBV T cell response and delayed HBV clearance in mice. Conclusions MMP2/9-mediated sCD100 release plays an important role in regulating intrahepatic anti-HBV CD8 T cell responses, thus mediating subsequent viral clearance during HBV infection. Lay summary Chronic hepatitis B virus (HBV) infection is still a major public health problem worldwide. The clearance of HBV relies largely on an effective T cell immune response, which usually becomes dysregulated in chronic HBV infection. Our work demonstrates that during acute-resolving HBV infection, the liver produces increased amounts of matrix metalloproteinases, which mediates membrane CD100 shedding from the surface of T cells and increases serum soluble CD100 levels. Soluble CD100 induces the activation of antigen presenting cells in the spleen and liver, and thus promotes the intrahepatic anti-HBV T cell response. This process has been compromised during chronic HBV infection. Our study provides a new mechanism to elucidate HBV persistence and a new target for developing immunotherapy strategies in chronically HBV infected patients.