Enhanced cross-presentation and improved CD8+ T cell responses after mannosylation of synthetic long peptides in mice

Judith Rauen; Christoph Kreer; Arlette Paillard; Suzanne van Duikeren; Willemien E Benckhuijsen; Marcel G Camps; A Rob P M Valentijn; Ferry Ossendorp; Jan W Drijfhout; Ramon Arens; Sven Burgdorf

doi:10.1371/journal.pone.0103755

Enhanced cross-presentation and improved CD8+ T cell responses after mannosylation of synthetic long peptides in mice

PLoS One. 2014 Aug 19;9(8):e103755. doi: 10.1371/journal.pone.0103755. eCollection 2014.

Affiliations

¹ Life and Medical Sciences Institute, University of Bonn, Bonn, Germany.
² Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
³ Department of Bio-organic Synthesis, Leiden University Medical Center, Leiden, the Netherlands.
⁴ Life and Medical Sciences Institute, University of Bonn, Bonn, Germany; Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Animals
Antigen Presentation
Antigen-Presenting Cells / cytology
Antigen-Presenting Cells / immunology*
Antigens / chemistry
Antigens / immunology*
Cell Proliferation
Chickens
Cross-Priming*
Endosomes / immunology
Endosomes / metabolism
Gene Expression
Immunity, Cellular / drug effects*
Lectins, C-Type / genetics
Lectins, C-Type / immunology
Mannose / immunology*
Mannose / metabolism
Mannose Receptor
Mannose-Binding Lectins / genetics
Mannose-Binding Lectins / immunology
Mice
Mice, Knockout
Molecular Sequence Data
Ovalbumin / chemistry
Ovalbumin / immunology
Papillomavirus E7 Proteins / chemistry
Papillomavirus E7 Proteins / immunology
Peptides / administration & dosage
Peptides / chemical synthesis
Peptides / immunology*
Protein Transport
Receptors, Cell Surface / genetics
Receptors, Cell Surface / immunology
Sequence Alignment
T-Lymphocytes, Cytotoxic / cytology
T-Lymphocytes, Cytotoxic / immunology*
T-Lymphocytes, Cytotoxic / metabolism

Substances

Antigens
Lectins, C-Type
Mannose Receptor
Mannose-Binding Lectins
Papillomavirus E7 Proteins
Peptides
Receptors, Cell Surface
oncogene protein E7, Human papillomavirus type 16
Ovalbumin
Mannose

Grants and funding

This work was supported by grant C1 of the collaborative research center 645 of the German research Foundation (DFG) to SB and by a Gisela Thier grant from LUMC to RA. SB is a member of the DFG Excellence cluster ImmunoSensation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.