Abstract
Viral escape from CD8+ cytotoxic T lymphocyte responses correlates with disease progression and represents a significant challenge for vaccination. Here, we demonstrate that CD8+ T cell recognition of the naturally occurring MHC-I-restricted LCMV-associated immune escape variant Y4F is restored following vaccination with a proline-altered peptide ligand (APL). The APL increases MHC/peptide (pMHC) complex stability, rigidifies the peptide and facilitates T cell receptor (TCR) recognition through reduced entropy costs. Structural analyses of pMHC complexes before and after TCR binding, combined with biophysical analyses, revealed that although the TCR binds similarly to all complexes, the p3P modification alters the conformations of a very limited amount of specific MHC and peptide residues, facilitating efficient TCR recognition. This approach can be easily introduced in peptides restricted to other MHC alleles, and can be combined with currently available and future vaccination protocols in order to prevent viral immune escape.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antiviral Agents / metabolism
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / metabolism*
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CD8-Positive T-Lymphocytes / physiology
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DNA-Binding Proteins / immunology
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Epitopes / immunology
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Epitopes, T-Lymphocyte / immunology
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Genes, RAG-1 / immunology
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Ligands
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Lymphocyte Activation / immunology
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Lymphocytic choriomeningitis virus / genetics
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Lymphocytic choriomeningitis virus / immunology*
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Lymphocytic choriomeningitis virus / pathogenicity
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Peptides / metabolism
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Proline / metabolism
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Protein Binding
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Receptors, Antigen, T-Cell / immunology*
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T-Lymphocytes, Cytotoxic / immunology
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Vaccination / methods
Substances
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Antiviral Agents
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DNA-Binding Proteins
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Epitopes
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Epitopes, T-Lymphocyte
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Ligands
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Peptides
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Rag2 protein, mouse
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Receptors, Antigen, T-Cell
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Proline
Grants and funding
This work was funded by the Swedish Research Council (2018-02874) and The Swedish Cancer Society CAN (2018/603) to AA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.