Pathogenic role for virus-specific CD4 T cells in mice with coronavirus-induced acute encephalitis.
Acute viral encephalitis is believed to result from direct virus destruction of infected cells and from virus-induced host immune response, but the relative contribution of each remains largely unknown. For example, C57BL/6 (B6) mice infected with mouse hepatitis virus (JHM strain, JHMV) develop severe encephalitis, with death occurring within 7 days. Here, we show that the host response to a single JHMV-specific immunodominant CD4 T-cell epitope is critical for severe disease. We engineered a recombinant JHMV with mutations in the immunodominant CD4 T-cell epitope (rJ.M(Y135Q)). Infection of naïve B6 mice with this virus resulted in mild disease with no mortality. However, introduction of a CD4 T-cell epitope from Listeria monocytogenes into rJ.M(Y135Q) generated a highly virulent virus. The decrease in disease severity was not due to a switch from Th1 to Th2 predominance in rJ.M(Y135Q)-infected mice, an effect on CD8 T-cell function, or differential expression of tumor necrosis factor-alpha by JHMV-specific CD4 T cells. These results show that the response to a single virus-specific CD4 T-cell epitope may contribute to a pathogenic host response in the setting of acute viral disease and that abrogation of this response ameliorates clinical disease without diminishing virus clearance.
Anghelina
Daniela
D
Department of Pediatrics, University of Iowa, Medical Laboratories 2042, Iowa City, IA 52242, USA.
Pewe
Lecia
L
Perlman
Stanley
S
D000818:Animals; D001921:Brain / Q000276:immunology / Q000821:virology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D003333:Coronaviridae Infections / Q000276:immunology*; D000086862:Coronavirus M Proteins; D018792:Encephalitis, Viral / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D006367:HeLa Cells; D006801:Humans; D016056:Immunodominant Epitopes / Q000235:genetics / Q000276:immunology; D008089:Listeria monocytogenes / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D006517:Murine hepatitis virus / Q000235:genetics / Q000276:immunology; D009154:Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014763:Viral Matrix Proteins / Q000235:genetics / Q000276:immunology*
D000086862:Coronavirus M Proteins; D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; D014763:Viral Matrix Proteins