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

  • Author Footnotes
    † These authors contributed equally to this article.
    Shangqing Yang
    Footnotes
    † These authors contributed equally to this article.
    Affiliations
    Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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  • Author Footnotes
    † These authors contributed equally to this article.
    Lu Wang
    Footnotes
    † These authors contributed equally to this article.
    Affiliations
    Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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  • Wen Pan
    Affiliations
    Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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  • Wibke Bayer
    Affiliations
    Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen 45147, Germany
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  • Christine Thoens
    Affiliations
    Institute for Virology, Heinrich-Heine-University, University Hospital, Duesseldorf 40225, Germany
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  • Kathrin Heim
    Affiliations
    Department of Medicine II, University Hospital Freiburg, Freiburg 79110, Germany

    Faculty of Medicine, University of Freiburg, Freiburg 79110, Germany
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  • Ulf Dittmer
    Affiliations
    Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen 45147, Germany
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  • Joerg Timm
    Affiliations
    Institute for Virology, Heinrich-Heine-University, University Hospital, Duesseldorf 40225, Germany
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  • Qin Wang
    Affiliations
    Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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  • Qing Yu
    Affiliations
    Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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  • Jinzhuo Luo
    Affiliations
    Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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  • Yanan Liu
    Affiliations
    Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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  • Maike Hofmann
    Affiliations
    Department of Medicine II, University Hospital Freiburg, Freiburg 79110, Germany

    Faculty of Medicine, University of Freiburg, Freiburg 79110, Germany
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  • Robert Thimme
    Affiliations
    Department of Medicine II, University Hospital Freiburg, Freiburg 79110, Germany

    Faculty of Medicine, University of Freiburg, Freiburg 79110, Germany
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  • Xiaoyong Zhang
    Affiliations
    Hepatology Unit and Key Laboratory for Organ Failure Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510551, China
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  • Hongtao Chen
    Affiliations
    Department of Infectious Diseases, The Second Clinical Medical College, Jinan University, Shenzhen 510632, China
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  • Hua Wang
    Affiliations
    Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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  • Xuemei Feng
    Affiliations
    Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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  • Xuecheng Yang
    Affiliations
    Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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  • Yinping Lu
    Affiliations
    Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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  • Mengji Lu
    Affiliations
    Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen 45147, Germany
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  • Author Footnotes
    † These authors contributed equally to this article.
    Dongliang Yang
    Footnotes
    † These authors contributed equally to this article.
    Affiliations
    Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
    Search for articles by this author
  • Author Footnotes
    † These authors contributed equally to this article.
    Jia Liu
    Correspondence
    Corresponding author: Address: Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue, 1277, Wuhan 430022, China. Tel: +86 1 86 96 15 98 26.
    Footnotes
    † These authors contributed equally to this article.
    Affiliations
    Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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  • Author Footnotes
    † These authors contributed equally to this article.

      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

      Keywords

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