Prolongation of prion disease-associated symptomatic phase relates to CD3+ T cell recruitment into the CNS in murine scrapie-infected mice.

Abstract Prion diseases are caused by the transconformation of the host cellular prion protein PrP c into an infectious neurotoxic isoform called PrP Sc . While vaccine-induced PrP-specific CD4 + T cells and antibodies partially protect scrapie-infected mice from disease, the potential autoreactivity of CD8 + cytotoxic T lymphocytes (CTLs) received little attention. Beneficial or pathogenic influence of PrP c -specific CTL was evaluated by stimulating a CD8 + T-cell-only response against PrP in scrapie-infected C57BL/6 mice. To circumvent immune tolerance to PrP, five PrP-derived nonamer peptides identified using prediction algorithms were anchored-optimized to improve binding affinity for H-2D b and immunogenicity (NP-peptides). All of the NP-peptides elicited a significant number of IFNγ secreting CD8 + T cells that better recognized the NP-peptides than the natives; three of them induced T cells that were lytic in vivo for NP-peptide-loaded target cells. Peptides 168 and 192 were naturally processed and presented by the 1C11 neuronal cell line. Minigenes encoding immunogenic NP-peptides inserted into adenovirus (rAds) vectors enhanced the specific CD8 + T-cell responses. Immunization with rAd encoding 168NP before scrapie inoculation significantly prolonged the survival of infected mice. This effect was attributable to a significant lengthening of the symptomatic phase and was associated with enhanced CD3 + T cell recruitment to the CNS. However, immunization with Ad168NP in scrapie-incubating mice induced IFNγ-secreting CD8 + T cells that were not cytolytic in vivo and did not influence disease progression nor infiltrated the brain. In conclusion, the data suggest that vaccine-induced PrP-specific CD8 + T cells interact with prions into the CNS during the clinical phase of the disease.