title: 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.
authors.affiliation: UMR-S 938, Hôpital St-Antoine, Bât. R. Kourilsky, 184 rue du Fg St-Antoine, 75012 Paris, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Sacquin
authors.forename: Thomas
authors.initials: T
authors.lastname: Chaigneau
authors.forename: Valérie
authors.initials: V
authors.lastname: Defaweux
authors.forename: Micheline
authors.initials: M
authors.lastname: Adam
authors.forename: Benoit
authors.initials: B
authors.lastname: Schneider
authors.forename: Martine
authors.initials: M
authors.lastname: Bruley Rosset
authors.forename: Marc
authors.initials: M
authors.lastname: Eloit
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002470:Cell Survival; D002490:Central Nervous System / Q000276:immunology / Q000473:pathology*; D002860:Chromium Radioisotopes; D005455:Fluorescent Antibody Technique; D007114:Immunization; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010455:Peptides / Q000276:immunology; D010957:Plasmids / Q000235:genetics; D018621:PrPC Proteins / Q000235:genetics / Q000276:immunology; D017096:Prion Diseases / Q000276:immunology*; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000276:immunology*; D012608:Scrapie / Q000276:immunology / Q000473:pathology*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D002860:Chromium Radioisotopes; D010455:Peptides; D018621:PrPC Proteins; D017260:Receptor-CD3 Complex, Antigen, T-Cell