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Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Northwestern University Medical School, Chicago, IL 60611
Theiler’s murine encephalomyelitis virus (TMEV)-induced
demyelinating disease is a chronic-progressive, immune-mediated CNS
demyelinating disease and a relevant model of multiple sclerosis.
Myelin destruction is initiated by TMEV-specific CD4+ T
cells targeting persistently infected CNS-resident APCs leading to
activation of myelin epitope-specific CD4+ T cells via
epitope spreading. We examined the temporal development of virus- and
myelin-specific T cell responses and acquisition of virus and myelin
epitopes by CNS-resident APCs during the chronic disease course.
CD4+ T cell responses to virus epitopes arise within 1 wk
after infection and persist over a >300-day period. In contrast,
myelin-specific T cell responses are first apparent 
50–60 days
postinfection, appear in an ordered progression associated with their
relative encephalitogenic dominance, and also persist. Consistent with
disease initiation by virus-specific CD4+ T cells, CNS
mononuclear cells from TMEV-infected SJL mice endogenously process and
present virus epitopes throughout the disease course, while myelin
epitopes are presented only after initiation of myelin damage (>50–60
days postinfection). Activated F4/80+ APCs expressing high
levels of MHC class II and B7 costimulatory molecules and ingested
myelin debris chronically accumulate in the CNS. These results suggest
a process of autoimmune induction in which virus-specific T
cell-mediated bystander myelin destruction leads to the recruitment and
activation of infiltrating and CNS-resident APCs that process and
present endogenous myelin epitopes to autoreactive T cells in a
hierarchical order.
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