title: Chemical Modification of Influenza CD8+ T-Cell Epitopes Enhances Their Immunogenicity Regardless of Immunodominance.
abstract: T cells are essential players in the defense against infection. By targeting the MHC class I antigen-presenting pathway with peptide-based vaccines, antigen-specific T cells can be induced. However, low immunogenicity of peptides poses a challenge. Here, we set out to increase immunogenicity of influenza-specific CD8+ T cell epitopes. By substituting amino acids in wild type sequences with non-proteogenic amino acids, affinity for MHC can be increased, which may ultimately enhance cytotoxic CD8+ T cell responses. Since preventive vaccines against viruses should induce a broad immune response, we used this method to optimize influenza-specific epitopes of varying dominance. For this purpose, HLA-A*0201 epitopes GILGFVFTL, FMYSDFHFI and NMLSTVLGV were selected in order of decreasing MHC-affinity and dominance. For all epitopes, we designed chemically enhanced altered peptide ligands (CPLs) that exhibited greater binding affinity than their WT counterparts; even binding scores of the high affinity GILGFVFTL epitope could be improved. When HLA-A*0201 transgenic mice were vaccinated with selected CPLs, at least 2 out of 4 CPLs of each epitope showed an increase in IFN-γ responses of splenocytes. Moreover, modification of the low affinity epitope NMLSTVLGV led to an increase in the number of mice that responded. By optimizing three additional influenza epitopes specific for HLA-A*0301, we show that this strategy can be extended to other alleles. Thus, enhancing binding affinity of peptides provides a valuable tool to improve the immunogenicity and range of preventive T cell-targeted peptide vaccines.
authors.affiliation: Centre for Infectious Disease Control (Cib), National Institute for Public Health and the Environment, Bilthoven, the Netherlands.
authors.forename: Sietske K
authors.initials: SK
authors.lastname: Rosendahl Huber
authors.affiliation: Division of Cell Biology, Netherlands Cancer Institute, Amsterdam, the Netherlands.|Institute for Chemical Immunology (ICI), Utrecht, the Netherlands.
authors.forename: Jolien J
authors.initials: JJ
authors.lastname: Luimstra
authors.affiliation: Centre for Infectious Disease Control (Cib), National Institute for Public Health and the Environment, Bilthoven, the Netherlands.
authors.forename: Josine
authors.initials: J
authors.lastname: van Beek
authors.affiliation: Division of Cell Biology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Rieuwert
authors.initials: R
authors.lastname: Hoppes
authors.affiliation: Centre for Infectious Disease Control (Cib), National Institute for Public Health and the Environment, Bilthoven, the Netherlands.
authors.forename: Ronald H J
authors.initials: RH
authors.lastname: Jacobi
authors.affiliation: Centre for Infectious Disease Control (Cib), National Institute for Public Health and the Environment, Bilthoven, the Netherlands.
authors.forename: Marion
authors.initials: M
authors.lastname: Hendriks
authors.affiliation: Division of Cell Biology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Kim
authors.initials: K
authors.lastname: Kapteijn
authors.affiliation: Division of Cell Biology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Casper
authors.initials: C
authors.lastname: Ouwerkerk
authors.affiliation: Division of Cell Biology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Boris
authors.initials: B
authors.lastname: Rodenko
authors.affiliation: Division of Cell Biology, Netherlands Cancer Institute, Amsterdam, the Netherlands.|Institute for Chemical Immunology (ICI), Utrecht, the Netherlands.
authors.forename: Huib
authors.initials: H
authors.lastname: Ovaa
authors.affiliation: Centre for Infectious Disease Control (Cib), National Institute for Public Health and the Environment, Bilthoven, the Netherlands.
authors.forename: Jørgen
authors.initials: J
authors.lastname: de Jonge
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology*; D005434:Flow Cytometry; D005454:Fluorescence Polarization; D015789:HLA-A2 Antigen / Q000276:immunology; D015791:HLA-A3 Antigen / Q000276:immunology; D006801:Humans; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000276:immunology*; D007251:Influenza, Human / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008822:Mice, Transgenic; D009976:Orthomyxoviridae Infections / Q000276:immunology; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D014611:Vaccination
chemical_list: D000596:Amino Acids; D018984:Epitopes, T-Lymphocyte; C435939:HLA-A*02:01 antigen; C442141:HLA-A*03:01 antigen; D015789:HLA-A2 Antigen; D015791:HLA-A3 Antigen; D016056:Immunodominant Epitopes; D010455:Peptides