Inverted immunodominance and impaired cytolytic function of CD8(+) T cellsduring viral persistence in the central nervous system

Mice infected with the neurotropic JHM strain of mouse hepatitis virus (JHM V) clear infectious virus; nevertheless, virus persists in the CNS as nonin fectious RNA, resulting in ongoing primary demyelination, Phenotypic and fu nctional analysis of CNS infiltrating cells during acute infection revealed a potent regional CD8(+) T cell response comprising up to 50% virus-specif ic T cells. The high prevalence of virus-specific T cells correlated with e x vivo cytolytic activity and efficient reduction in viral titers, Progress ive viral clearance coincided with the loss of cytolytic activity, but rete ntion of IFN-gamma secretion and increased expression of the early activati on marker CD69, indicating differential regulation of effector function, Al though the total number of infiltrating T cells declined following clearanc e of infectious virus, CD8(+) T cells, both specific for the dominant viral epitopes and of unknown specificity, were retained within the CNS, suggest ing an ongoing T cell response during persistent CNS infection involving a virus-independent component. Reversed immunodominance within the virus-spec ific CD8(+) T cell population further indicated epitope-specific regulation , supporting ongoing T cell activation, Even in the absence of infectious v irus, the CNS thus provides an environment that maintains both unspecific a nd Ag-specific CD8(+) T cells with restricted effector function. Chronic T cell stimulation may thus play a role in preventing viral recrudescence, wh ile increasing the risk of pathological conditions, such as demyelination.