title: Recovery from mouse hepatitis virus infection depends on recruitment of CD8(+) cells rather than activation of intrahepatic CD4(+)alphabeta(-)TCR(inter) or NK-T cells.
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(+)alphabeta - TCR(inter) cells decreased in both virally infected groups of mice, while CD4(+)alphabeta - TCR(inter) LFA-1(high) 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(+)alphabeta - TCR(inter) 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(+)alphabeta - TCR(inter) 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.
authors.affiliation: Département des Sciences Biologiques, Université du Québec à Montréal, Montréal, H3C 3P8, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Lamontagne
authors.forename: S
authors.initials: S
authors.lastname: Lusignan
authors.forename: C
authors.initials: C
authors.lastname: Page
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D018352:Coronavirus Infections / Q000276:immunology*; D006524:Hepatitis, Viral, Animal / Q000276:immunology*; D007108:Immune Tolerance; D007694:Killer Cells, Natural / Q000276:immunology*; D008099:Liver / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D006517:Murine hepatitis virus; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D013154:Spleen / Q000276:immunology
chemical_list: D016693:Receptors, Antigen, T-Cell, alpha-beta