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Chemical Modification of Influenza CD8+ T-Cell Epitopes Enhances Their Immunogenicity Regardless of Immunodominance.
- Source :
-
PloS one [PLoS One] 2016 Jun 22; Vol. 11 (6), pp. e0156462. Date of Electronic Publication: 2016 Jun 22 (Print Publication: 2016). - Publication Year :
- 2016
-
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.
- Subjects :
- Amino Acid Sequence
Amino Acids chemistry
Animals
Epitopes, T-Lymphocyte chemistry
Flow Cytometry
Fluorescence Polarization
HLA-A2 Antigen immunology
HLA-A3 Antigen immunology
Humans
Immunodominant Epitopes chemistry
Lymphocyte Activation immunology
Mice, Transgenic
Orthomyxoviridae Infections immunology
Peptides chemistry
Protein Binding
Vaccination
CD8-Positive T-Lymphocytes immunology
Epitopes, T-Lymphocyte immunology
Immunodominant Epitopes immunology
Influenza, Human immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 11
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 27333291
- Full Text :
- https://doi.org/10.1371/journal.pone.0156462