CD8+ T cells directed against a viral peptide contribute to loss of motor function by disrupting axonal transport in a viral model of fulminant demyelination.
Demyelination, a pathological hallmark of multiple sclerosis, may be a necessary but not a sufficient condition for motor dysfunction associated with this disease. We favor a neurodegenerative model of multiple sclerosis and suggest that demyelination creates a permissive environment wherein the denuded axon becomes susceptible to immune-mediated injury. Unfortunately, the cellular effectors responsible for eliciting such axonal injury are currently unknown. Based on previous observations implicating cytotoxic T cells in this injury, we assessed motor function, axon dropout, and axon injury following peptide depletion of the immunodominant CD8+ antiviral T cell response in the IFNgamma receptor-deficient mouse model of acute demyelination. We found that the targeted removal of this population of cytotoxic effector cells prior to infection with the Theiler's murine encephalomyelitis virus caused a substantial preservation of motor function at 45 days postinfection that was associated with preservation of retrograde axonal transport in a subpopulation of surviving axons within the spinal cord. We conclude that cytotoxic T cells may be responsible for the initiation of axon injury following demyelination.
Howe
Charles L
CL
Department of Neuroscience, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. howe.charles@mayo.edu <howe.charles@mayo.edu>
Ure
Daren
D
Adelson
Jaimie D
JD
LaFrance-Corey
Reghann
R
Johnson
Aaron
A
Rodriguez
Moses
M
D000704:Analysis of Variance; D000818:Animals; D001370:Axonal Transport / Q000187:drug effects / Q000502:physiology*; D001369:Axons / Q000473:pathology; D001522:Behavior, Animal; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D036022:Capsid Proteins / Q000009:adverse effects*; D018188:Cardiovirus Infections / Q000150:complications*; D003711:Demyelinating Diseases / Q000209:etiology* / Q000473:pathology / Q000821:virology; D004195:Disease Models, Animal; D005434:Flow Cytometry; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D017471:Receptors, Interferon / Q000172:deficiency; D045442:Rotarod Performance Test / Q000379:methods; D016622:Silver Staining / Q000379:methods; D000096743:Interferon gamma Receptor
D036022:Capsid Proteins; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor; C442556:VP2 protein, Theilovirus