Highlights
- •HBV infection results in altered mCD100 expression and serum sCD100 levels.
- •sCD100 can increase anti-HBV CTL response and accelerate HBV clearance.
- •mCD100 shedding and sCD100 formation is mediated by MMP2 and MMP9.
- •CHB patients show decreased serum MMP2 and sCD100 levels.
- •MMP2/9 inhibition suppresses anti-HBV CTL response and delays HBV clearance.
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 have important immune regulatory functions that promote
immune cell activation and responses. This study investigated 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 analysed in patients with chronic HBV (CHB) and in HBV-replicating
mice. The ability of sCD100 to mediate antigen-presenting cell maturation, HBV-specific
T cell activation, and HBV clearance were analysed in HBV-replicating mice and patients
with CHB.
Results
Patients with CHB had higher mCD100 expression on T cells and lower serum sCD100 levels
compared with healthy controls. Therapeutic sCD100 treatment resulted in the activation
of DCs and liver sinusoidal endothelial cells, enhanced HBV-specific CD8 T cell responses,
and accelerated HBV clearance, whereas 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. Patients with CHB had significantly lower serum
MMP2 levels, which positively correlated with serum sCD100 levels, compared with healthy
controls. 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 has 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 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 study provides a new mechanism
to elucidate HBV persistence and a new target for developing immunotherapy strategies
in patients chronically infected with HBV.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: June 04, 2019
Accepted:
May 14,
2019
Received in revised form:
April 30,
2019
Received:
October 10,
2018
Identification
Copyright
© 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
