The immunodominant CD8+ T cell epitope region of Theiler's virus in resistant C57BL/6 mice is critical for anti-viral immune responses, viral persistence, and binding to the host cells.
Theiler's virus infection induces an immune-mediated demyelinating disease, providing a relevant animal model of human multiple sclerosis. VP2(121-130)-specific CD8+ T cells in resistant H-2b mice account for the majority of CNS-infiltrating CD8+ T cells. To further study the role of the CD8(+) T cells, we generated a panel of mutant viruses substituted with L, G, or T at the anchor residue (M130) of the VP2(121-130) epitope. M130L virus (M130L-V) with a substitution of M with L displayed similar properties as wild-type virus (WT-V). However, M130G-V and M130T-V could not establish a persistent infection in the CNS. The level of both virus-specific CD8+ and CD4+ T cell responses is significantly reduced in mice infected with these variant viruses. While all mutant and wild-type viruses replicate comparably in BHK cells, replication of M130G-V and M130T-V in macrophages was significantly lower compared to those infected with WT-V and M130L-V. Interestingly, these mutant viruses deficient in replication in primary mouse cells showed drastically reduced binding ability to the cells. These results suggest that the anchor residue of the predominant CD8+ T cell epitope of TMEV in resistant mice is critical for the virus to infect target cells and this deficiency may result in poor viral persistence leading to correspondingly low T cell responses in the periphery and CNS. Thus, selection of the cellular binding region of the virus as the predominant epitope for CD8+ T cells in resistant mice may provide a distinct advantage in controlling viral persistence by preventing escape mutations.
Myoung
Jinjong
J
Department of Microbiology-Immunology, Northwestern University Medical School, 303 East Chicago Ave., Chicago, IL 60611, USA.
Hou
Wanqiu
W
Kang
Bongsu
B
Lyman
Michael A
MA
Kang
Jeong-Ah
JA
Kim
Byung S
BS
D000818:Animals; D001921:Brain / Q000276:immunology / Q000821:virology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D036022:Capsid Proteins / Q000276:immunology*; D002460:Cell Line; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D005260:Female; D006183:H-2 Antigens / Q000276:immunology; D064532:Histocompatibility Antigen H-2D; D016056:Immunodominant Epitopes / Q000276:immunology*; D008213:Lymphocyte Activation; D008264:Macrophages / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000209:etiology*; D009154:Mutation; D013116:Spinal Cord / Q000276:immunology / Q000821:virology; D017945:Theilovirus / Q000502:physiology*; D014779:Virus Replication
D036022:Capsid Proteins; D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; D016056:Immunodominant Epitopes; C442556:VP2 protein, Theilovirus