Contributions of CD8+ T cells and viral spread to demyelinating disease.
Acute and chronic demyelination are hallmarks of CNS infection by the neurotropic JHM strain of mouse hepatitis virus. Although infectious virus is cleared by CD8+ T cells, both viral RNA and activated CD8+ T cells remain in the CNS during persistence potentially contributing to pathology. To dissociate immune from virus-mediated determinants initiating and maintaining demyelinating disease, mice were infected with two attenuated viral variants differing in a hypervariable region of the spike protein. Despite similar viral replication and tropism, one infection was marked by extensive demyelination and paralysis, whereas the other resulted in no clinical symptoms and minimal neuropathology. Mononuclear cells from either infected brain exhibited virus specific ex vivo cytolytic activity, which was rapidly lost during viral clearance. As revealed by class I tetramer technology the paralytic variant was superior in inducing specific CD8+ T cells during the acute disease. However, after infectious virus was cleared, twice as many virus-specific IFN-gamma-secreting CD8+ T cells were recovered from the brains of asymptomatic mice compared with mice undergoing demyelination, suggesting that IFN-gamma ameliorates rather than perpetuates JHM strain of mouse hepatitis virus-induced demyelination. The present data thus indicate that in immunocompetent mice, effector CD8+ T cells control infection without mediating either clinical disease or demyelination. In contrast, demyelination correlated with early and sustained infection of the spinal cord. Rapid viral spread, attributed to determinants within the spike protein and possibly perpetuated by suboptimal CD8+ T cell effector function, thus ultimately leads to the process of immune-mediated demyelination.
Marten
N W
NW
Departments of Neurology, Molecular Microbiology and Immunology, and Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Stohlman
S A
SA
Atkinson
R D
RD
Hinton
D R
DR
Fleming
J O
JO
Bergmann
C C
CC
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002908:Chronic Disease; D018352:Coronavirus Infections / Q000209:etiology / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D003711:Demyelinating Diseases / Q000209:etiology / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D006517:Murine hepatitis virus / Q000276:immunology / Q000472:pathogenicity*; D010243:Paralysis / Q000276:immunology / Q000821:virology; D013116:Spinal Cord / Q000276:immunology / Q000473:pathology / Q000821:virology; D019562:Viral Load; D014779:Virus Replication / Q000276:immunology
D007371:Interferon-gamma