Abstract
Mouse hepatitis virus (MHV) provides an excellent animal model for the study of the immunopathological mechanisms involved in hepatic viral diseases. We previously generated an attenuated viral variant, YAC-MHV3, which induces a subclinical disease and recovery within 15 days. In contrast, the L2-MHV3 strain induces the development of a fulminant hepatitis, leading to death within 3 days. In this paper, we document intrahepatic and splenic T cell subpopulations involved in the hepatitis process and viral elimination identified in attenuated or pathogenic MHV3-infected C57BL/6 mice. Percentages of intrahepatic CD4+ cells decreased in attenuated YAC-MHV3-infected mice, while they increased in mice infected with pathogenic L2-MHV3, compared with uninfected animals. Moreover, in YAC-MHV3-infected mice, the percentages of intrahepatic CD8+ cells slightly decreased at 24 h pi, then increased until 15 days pi. In contrast, the CD4/CD8 ratios of splenic lymphoid subpopulations increased in the first days of infection and returned to normal values at 15 days pi. Intrahepatic NK1.1+αβ − TCRinter cells decreased in both virally infected groups of mice, while CD4+αβ − TCRinter LFA-1high cells increased in L2-MHV3-infected mice, in contrast with what was seen in YAC-MHV3-infected mice. However, these cells became anergic following Con A or PHA stimulation. Ex vivo studies showed that only the intrahepatic CD8+ cells that were increased in YAC-MHV3-infected mice could be stimulated by lectins. In addition, in vitro viral infections revealed that L2-MHV3 viral infection led to an increase of intrahepatic CD4+αβ − TCRinter cells in the absence of CD8+ cells only. These results indicate that the attenuated phenotype of the YAC-MHV3 virus is related to two different mechanisms: the first involves no increase of intrahepatic CD4+αβ − TCRinter or NK-T cells, while the second favors the recruitment and activation of CD8+ cells in liver. The results are discussed in relation to the integrity of intrahepatic immune tolerance mechanisms and immune-mediated viral elimination.
Keywords: MHV3, coronavirus, hepatitis, T lymphocytes, liver, suppression
References
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