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: Antoine Sacquin, Thomas Chaigneau, Valérie Defaweux, Micheline Adam, Benoit Schneider, Martine Bruley Rosset, Marc Eloit
• Journal: Brain, behavior, and immunity (Brain Behav Immun) Vol. 26 Issue 6 Pg. 919-30 (Aug 2012) ISSN: 1090-2139 [Electronic] Netherlands
• PMID: 22522067 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

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

Topics

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