Fas ligand interactions contribute to CD8+ T-cell-mediated control of West Nile virus infection in the central nervous system.
West Nile virus (WNV) is a neurotropic flavivirus that causes encephalitis, most frequently in elderly and immunocompromised humans. Previous studies demonstrated that CD8+ T cells utilize perforin-dependent cytolytic mechanisms to limit WNV infection. Nonetheless, the phenotype of perforin-deficient CD8+ T cells was not as severe as that of an absence of CD8+ T cells, suggesting additional effector control mechanisms. In this study, we evaluated the contribution of Fas-Fas ligand (FasL) interactions to CD8+ T-cell-mediated control of WNV infection. Notably, the cell death receptor Fas was strongly upregulated on neurons in culture and in vivo after WNV infection. gld mice that were functionally deficient in FasL expression showed increased susceptibility to lethal WNV infection. Although antigen-specific priming of CD8+ T cells in peripheral lymphoid tissues was normal in gld mice, increased central nervous system (CNS) viral burdens and delayed clearance were observed. Moreover, the adoptive transfer of WNV-primed wild-type but not gld CD8+ T cells to recipient CD8(-/-) or gld mice efficiently limited infection in the CNS and enhanced survival rates. Overall, our data suggest that CD8+ T cells also utilize FasL effector mechanisms to contain WNV infection in Fas-expressing neurons in the CNS.
Shrestha
Bimmi
B
Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Diamond
Michael S
MS
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism* / Q000821:virology; D002494:Central Nervous System Infections / Q000821:virology*; D006224:Cricetinae; D053222:Fas Ligand Protein / Q000378:metabolism / Q000502:physiology*; D015967:Gene Expression Regulation, Viral; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism; D014901:West Nile Fever / Q000821:virology*; D014902:West Nile virus / Q000378:metabolism