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The Journal of Immunology, 1999, 163: 3379-3387.
Copyright © 1999 by The American Association of Immunologists

Inverted Immunodominance and Impaired Cytolytic Function of CD8+ T Cells During Viral Persistence in the Central Nervous System1

Cornelia C. Bergmann2,*,{dagger}, John D. Altman§, David Hinton*,{ddagger} and Stephen A. Stohlman*,{dagger}

Departments of * Neurology, {dagger} Molecular Microbiology and Immunology, and {ddagger} Pathology, University of Southern California School of Medicine, Los Angeles, CA 90033; and § Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322

Mice infected with the neurotropic JHM strain of mouse hepatitis virus (JHMV) clear infectious virus; nevertheless, virus persists in the CNS as noninfectious RNA, resulting in ongoing primary demyelination. Phenotypic and functional analysis of CNS infiltrating cells during acute infection revealed a potent regional CD8+ T cell response comprising up to 50% virus-specific T cells. The high prevalence of virus-specific T cells correlated with ex vivo cytolytic activity and efficient reduction in viral titers. Progressive viral clearance coincided with the loss of cytolytic activity, but retention of IFN-{gamma} secretion and increased expression of the early activation marker CD69, indicating differential regulation of effector function. Although the total number of infiltrating T cells declined following clearance of infectious virus, CD8+ T cells, both specific for the dominant viral epitopes and of unknown specificity, were retained within the CNS, suggesting an ongoing T cell response during persistent CNS infection involving a virus-independent component. Reversed immunodominance within the virus-specific CD8+ T cell population further indicated epitope-specific regulation, supporting ongoing T cell activation. Even in the absence of infectious virus, the CNS thus provides an environment that maintains both unspecific and Ag-specific CD8+ T cells with restricted effector function. Chronic T cell stimulation may thus play a role in preventing viral recrudescence, while increasing the risk of pathological conditions, such as demyelination.




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