Identification of two immunogenic domains of the prion protein—PrP—which activate class II-restricted T cells and elicit antibody responses against the native molecule

Abstract

Recent reports suggest that immunity against the prion protein (PrP) retards transmissible spongiform encephalopathies progression in infected mice. A major obstacle to the development of vaccines comes from the fact that PrP is poorly immunogenic, as it is seen as self by the host immune system. Additional questions concern the immune mechanisms involved in protection and the risk of eliciting adverse reactions in the central nervous system of treated patients. Peptide-based vaccines offer an attractive strategy to overcome these difficulties. We have undertaken the identification of the immunogenic regions of PrP, which trigger helper T cells (Th) associated with antibody production. Our results identify two main regions, one between the structured and flexible portion of PrP (98-127) and a second between alpha 1 and alpha 2 helix (143-187). Peptides (30-mer) corresponding to these regions elicit class II-restricted Th cells and antibody production against native PrP and could therefore be of potential interest for a peptide-based vaccination.

Breaking Immune Tolerance to the Prion Protein Using Prion Protein Peptides Plus Oligodeoxynucleotide-CpG in Mice

“…The three PrP peptides selected in the present study are naturally processed and presented by APC as shown after immunization of Prnp Ϫ/Ϫ mice with a plasmid encoding the entire PrP sequence (18). However, peptide immunization with CFA as adjuvant could not induce a detectable PrP-specific response in PrP ϩ mice.…”

“…C57BL/6 wild-type mice were immunized twice at 10-to 15-day intervals with P39-67, P98-127, P143-172, and P158-187 (Table I) together with either CFA or CpG in IFA. These four peptides were selected from 13 overlapping 30-mers because of their ability to stimulate a T cell response in Prnp Ϫ/Ϫ mice (18); all other peptides did not induce a detectable T cell proliferation. P39-67 was used as a negative control in further studies.…”

“…We previously found that immunizing Prnp Ϫ/Ϫ mice with plasmid DNA encoding mouse PrP could generate both T and B cell responses (18). Out of a library of 13 overlapping 30-mers encompassing the entire PrP sequence, three peptides only were able to stimulate in vitro CD4 T cell proliferation after in vivo priming of Prnp Ϫ/Ϫ mice with PrP-expressing plasmid DNA or PrP peptides in CFA.…”

Mouse vaccination with dendritic cells loaded with prion protein peptides overcomes tolerance and delays scrapie

“…PrP 97-128 and PrP 158-187 are two immunogenic peptides recognized by CD4 + T cells in a class II, I-A b context. They were previously identified out of a bank of 13 peptides, mostly 30-mers, with a 15 aa overlap on each side (Gregoire et al, 2004). The bank was synthesized by NeoMPS (Strasbourg, France) with a minimum of 80 % purity.…”

“…Immunization of mice made genetically deficient for PrP (Prnp 2/2 ) with PrP 97-128 induces moderate T-cell responses but good Ab secretion, including Abs to native, cell-bound PrPc, whereas PrP 158-187 elicits strong cellular responses but few Abs to the native protein (Gregoire et al, 2004). When injected into wt mice, the same peptides trigger no response unless they are administered together with a potent adjuvant such as CpG-ODN (Rosset et al, 2004 (Fig. 3b).…”