Abstract
Bacterially derived heat shock proteins have been shown to be powerful adjuvants of the immune response. Due to their ability to bind protein ligands, it has been shown that they can chaperone peptide epitopes for cross-presentation of antigen by dendritic cells (DC) to CD8+ lymphocytes. We have been able to elicit very powerful cyto-toxic T cell (CTL) responses by pulsing human monocyte derived DC with HSMO-peptide complexes. Free peptide alone or use of another adjuvant such as LPS with free peptide did not elicit such powerful responses. We have shown that peptidebinding fragments of HSP70, without a nuclcotide-binding domain, are as effective in eliciting this response. To quantify the efficiency of peptide delivered on HSP70 we determined the affinity of HSP70 for peptide by suface plasmon resonance and fluorescence anisotropy. Furthermore, the role of peptide binding to HSMO was investigated by site-directed mutagenesis of the substrate-binding pocket of HSP70. The V410F mutant, which cannot bind peptide, is unable to generate CTL even in the presence of excess free peptide, but is as good an adjuvant as wild-type HSP70. These data demonstrate a poweful method of eliciting human CTL responses by DC using HSP70 to deliver antigen and stimulate DC simultaneously. To our knowledge, this is the first instance that HSPchaperone antigens have been used to elicit a human CTL response. M153
Published Version
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