Abstract
The use of synthetic long peptides (SLP) has been proven to be a promising approach to induce adaptive immune responses in vaccination strategies. Here, we analyzed whether the efficiency to activate cytotoxic T cells by SLP-based vaccinations can be increased by conjugating SLPs to mannose residues. We could demonstrate that mannosylation of SLPs results in increased internalization by the mannose receptor (MR) on murine antigen-presenting cells. MR-mediated internalization targeted the mannosylated SLPs into early endosomes, from where they were cross-presented very efficiently compared to non-mannosylated SLPs. The influence of SLP mannosylation was specific for cross-presentation, as no influence on MHC II-restricted presentation was observed. Additionally, we showed that vaccination of mice with mannosylated SLPs containing epitopes from either ovalbumin or HPV E7 resulted in enhanced proliferation and activation of antigen-specific CD8+ T cells. These findings demonstrate that mannosylation of SLPs augments the induction of a cytotoxic T cell response in vitro and in vivo and might be a promising approach to induce cytotoxic T cell responses in e.g. cancer therapy and anti-viral immunity.
Highlights
Both prophylactic and therapeutic vaccinations are successful approaches to induce humoral and cellular adaptive immune responses aiming to control infectious pathogens and cancerous cells [1]
This uptake was comparable to the internalization of OVA, which is highly mannosylated in its natural form [21], indicating that mannosylation of synthetic long peptides (SLP) results in enhanced uptake
Since the mannose receptor (MR) targets its ligands towards a non-degradative subset of early endosomes [17,26,27], from where processing for crosspresentation efficiently can take place [18,19], the MR seems to be an optimal target for vaccination purposes aimed at the induction of a cytotoxic CD8+ T cell response [28,29]
Summary
Both prophylactic and therapeutic vaccinations are successful approaches to induce humoral and cellular adaptive immune responses aiming to control infectious pathogens and cancerous cells [1]. Immunity against certain (persistent) intracellular bacteria and viruses as well as most cancers, relies highly on the activation of antigen-specific CD4+ and CD8+ T cells, which requires different types of vaccines [2] To this end, diverse (therapeutic) vaccine methodologies have been developed with varying success that aim to mount a robust and effective T cell response with the ultimate aim to prevent and/or treat infections and cancers. Vaccination with synthetic long peptides (SLPs), covering viral or tumor epitopes, has shown promising results in experimental models and recently in clinical therapeutic vaccination trials [3] This peptide-based vaccine platform allows covering multiple (overlapping) MHC classes I and II epitopes and does not require the necessity for HLA-typing for each patient to be treated [4,5]. Mechanistic studies with peptide vaccines in different experimental models revealed that by more specific targeting, improving the uptake of SLPs, and/or activation of APCs the SLP-based vaccines generally advance leading to better clinical success [5]
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