| Summary: | 博士 === 國立臺灣大學 === 免疫學研究所 === 101 === Elevated liver enzyme level is an outstanding feature in patients with dengue. However, the pathogenic mechanism of liver injury has not been clearly demonstrated. In this study, employing a mouse model, we uncovered the immunopathogenic mechanism in dengue virus-induced liver injury. Immunocompetent C57BL/6 mice were infected intravenously with dengue virus strain 16681. Infected mice had transient viremia, detectable viral capsid gene and cleaved caspase 3 in the liver. In the mean time, NK cell and T cell infiltrations peaked at days 1 and 5, respectively. Neutralizing CXCL10 or depletion of Asialo GM1+ cells reduced levels of liver enzymes, cleaved caspase 3 and TUNEL+ cells in the liver at day 1 after infection. Liver cell death is reduced in NK cell cytotoxic function-deficient STAT1 KO mice at day 1 after infection. Perforin is partially involved in NK cell-mediated liver cell death. Both CD4+ and CD8+ T cells infiltrated into the liver at later time point and at which time intrahepatic leukocytes (IHL) exhibited antigen-specific cytotoxicity against DENV-infected targets. Cleaved caspase 3 and TUNEL+ cells were diminished in mice with TCRβ deficiency and in those depleted of CD8+ T cells, respectively, at day 5 after infection. IHLs isolated from CD8-depleting mice lost cytotoxicity against infected targets. Moreover, intrahepatic CD8+ T cells were like their splenic counterparts recognized DENV NS4B99-107 peptide. Intrahepatic CD8+ T cell-mediated DENV-induced liver cell death is cell-cell contact-dependent but perforin-independent. Together, these results show that infiltrating NK and CD8+ T cells cause liver cell death. While NK cells were responsible for cell death at early time point of infection, CD8+ T cells were for later. CD8+ T cells that recognize NS4B99-107 constitute at least one of the major intrahepatic cytotoxic CD8+ T cell populations. This study provokes the new pathogenic role in dengue virus-infected patients.
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