Parenchymal expression of CD40 exacerbates adenovirus-induced hepatitis in mice

Authors

  • Jiabin Yan,

    1. Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX
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    • *

      These authors contributed equally to this work.

  • Zuliang Jie,

    1. Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX
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    • *

      These authors contributed equally to this work.

  • Lifei Hou,

    1. Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX
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  • Joao L. Wanderley,

    1. Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX
    2. Morphological Sciences Program, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
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  • Lynn Soong,

    1. Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX
    2. Department of Pathology, University of Texas Medical Branch, Galveston, TX
    3. Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX
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  • Shalini Gupta,

    1. Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX
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  • Suimin Qiu,

    1. Department of Pathology, University of Texas Medical Branch, Galveston, TX
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  • Tehsheng Chan,

    1. Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX
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  • Jiaren Sun

    Corresponding author
    1. Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX
    2. Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX
    • Department of Microbiology and Immunology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1019
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    • fax: 409-747-6869


  • Potential conflict of interest: Nothing to report.

Abstract

The healthy adult human liver expresses low levels of major histocompatibility complex class II (MHC II) and undetectable levels of immune costimulatory molecules. However, high levels of MHC II, CD40, and B7 family molecules are expressed in the activated Kupffer cells and hepatocytes of patients with viral hepatitis. The precise role of these molecules in viral clearance and immune-mediated liver injury is not well understood. We hypothesized that parenchymal CD40 expression enhances T cell recruitment and effector functions, which may facilitate viral clearance and alleviate liver injury. To test this hypothesis, we generated novel liver-specific, conditional CD40 transgenic mice, and we challenged them intravenously with a recombinant replication-deficient adenovirus carrying Cre recombinase (AdCre). Wild-type mice infected with AdCre developed a relatively mild course of viral hepatitis and recovered spontaneously. CD40 expression in the livers of transgenic animals, however, resulted in CD80 and CD86 expression. The dysregulation of population dynamics and effector functions of intrahepatic lymphocytes (IHLs) resulted in severe lymphocytic infiltration, apoptosis, necroinflammation, and serum alanine aminotransferase elevations in a dose-dependent fashion. To our surprise, an early expansion and subsequent contraction of IHLs (especially CD8+ and natural killer cells), accompanied by increased granzyme B and interferon-γ production, did not lead to faster viral clearance in CD40 transgenic mice. Conclusion: Our results demonstrate that hepatic CD40 expression does not accelerate adenoviral clearance but rather exacerbates liver injury. This study unveils a previously unknown deleterious effect of hepatic CD40 on adenovirus-induced liver inflammation. (Hepatology 2011;)

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