THEILERS VIRUS-INFECTION OF GENETICALLY SUSCEPTIBLE MICE INDUCES CENTRAL NERVOUS SYSTEM-INFILTRATING CTLS WITH NO APPARENT VIRAL OR MAJOR MYELIN ANTIGENIC SPECIFICITY

Intracranial infection of susceptible mice with Theiler's virus result s in persistent infection and spinal cord demyelination similar to hum an multiple sclerosis, While central nervous system infiltrating lymph ocytes (CNS-ILs) in these mice display no virus-specific CTL activity, the cells were found to be activated killers using a specificity-inde pendent assay. We previously demonstrated that the depletion of T cell s in persistently infected mice significantly decreases demyelinating disease. Consequently, we have investigated the killing pathways emplo yed by CNS-ILs that are isolated from persistently infected animals, t he relative contribution of CD4 and CD8 cells in the generation of the se CTLs, and the reactivity of this cell population to two putative au toantigens in the CNS, In vitro or in vivo manipulation of T cell popu lations using Abs or genetic knockout strategies demonstrate that the cytotoxic activity is primarily mediated by CD8(+) T cells, and that p erforin is an important molecule in the effector pathway. Since effect or functions in infected mice were not inhibited by the depletion of C D4 cells with mAb but was blocked genetically in CD4 knockout mice, CD 4(+) T cells appear to play a helper role in the generation of CD8(+) CTLs, We found no evidence of autoimmune-mediated demyelination, as th e CD8(+) CTLs were not reactive to two major myelin autoantigens, myel in basic protein and proteolipid protein. Our finding that CNS-ILs tha t are isolated from mice susceptible to persistent virus infection are neither specific for virus or myelin autoantigens is consistent with the possibility that CD8(+) CTLs mediate CNS damage as a result of non specific activation by virus.