Virus-induced immunosuppression: immune system-mediated destruction of virus-infected dendritic cells results in generalized immune suppression.
Despite the clinical importance of virus-induced immunosuppression, how virus infection may lead to a generalized suppression of the host immune response is poorly understood. To elucidate the principles involved, we analyzed the mechanism by which a lymphocytic choriomeningitis virus (LCMV) variant produces a generalized immune suppression in its natural host, the mouse. Whereas adult mice inoculated intravenously with LCMV Armstrong rapidly clear the infection and remain immunocompetent, inoculation with the Armstrong-derived LCMV variant clone 13, which differs from its parent virus at only two amino acid positions, by contrast results in persistent infection and a generalized deficit in responsiveness to subsequent immune challenge. Here we show that the immune suppression induced by LCMV clone 13 is associated with a CD8-dependent loss of interdigitating dendritic cells from periarteriolar lymphoid sheaths in the spleen and, functionally, with a deficit in the ability of splenocytes from infected mice to stimulate the proliferation of naive T cells in a primary mixed lymphocyte reaction. Dendritic cells are not depleted in immunocompetent Armstrong-infected mice. LCMV Armstrong and clone 13 exhibit differences in their tropism within the spleen, with clone 13 causing a higher level of infection of antigen-presenting cells in the white pulp, including periarterial interdigitating dendritic cells, than Armstrong, thereby rendering these cells targets for destruction by the antiviral CD8+ cytotoxic T-lymphocyte response which is induced at early times following infection with either virus. Our findings illustrate the key role that virus tropism may play in determining pathogenicity and, further, document a mechanism for virus-induced immunosuppression which may contribute to the clinically important immune suppression associated with many virus infections, including human immunodeficiency virus type 1.
Borrow
P
P
Department of Neuropharmacology, Scripps Research Institute, La Jolla, California 92037.
Evans
C F
CF
Oldstone
M B
MB
D000818:Animals; D000938:Antigen-Presenting Cells / Q000502:physiology; D016827:CD8 Antigens / Q000502:physiology; D006224:Cricetinae; D003713:Dendritic Cells / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology; D007108:Immune Tolerance; D008216:Lymphocytic Choriomeningitis / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D013154:Spleen / Q000821:virology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D016827:CD8 Antigens