Inverted immunodominance and impaired cytolytic function of CD8+ T cells during viral persistence in the central nervous system.
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.
Bergmann
C C
CC
Department of Neurology, University of Southern California School of Medicine, Los Angeles 90033, USA. cbergman@hsc.usc.edu
Altman
J D
JD
Hinton
D
D
Stohlman
S A
SA
D000208:Acute Disease; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000821:virology; D002490:Central Nervous System / Q000276:immunology / Q000821:virology*; D018352:Coronavirus Infections / Q000209:etiology / Q000276:immunology* / Q000821:virology; D003433:Crosses, Genetic; D003602:Cytotoxicity, Immunologic; D016056:Immunodominant Epitopes / Q000276:immunology*; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D006517:Murine hepatitis virus / Q000276:immunology* / Q000472:pathogenicity; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology / Q000821:virology; D019562:Viral Load; D014779:Virus Replication / Q000276:immunology
D016056:Immunodominant Epitopes