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

Brain Behav Immun. 2012 Aug;26(6):919-30. doi: 10.1016/j.bbi.2012.04.002. Epub 2012 Apr 13.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Survival
  • Central Nervous System / immunology
  • Central Nervous System / pathology*
  • Chromium Radioisotopes
  • Fluorescent Antibody Technique
  • Immunization
  • Immunohistochemistry
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Sequence Data
  • Peptides / immunology
  • Plasmids / genetics
  • PrPC Proteins / genetics
  • PrPC Proteins / immunology
  • Prion Diseases / immunology*
  • Receptor-CD3 Complex, Antigen, T-Cell / immunology*
  • Scrapie / immunology
  • Scrapie / pathology*
  • T-Lymphocytes / immunology*

Substances

  • Chromium Radioisotopes
  • Peptides
  • PrPC Proteins
  • Receptor-CD3 Complex, Antigen, T-Cell