Download MendeleyIdentification of a superagonist variant of the immunodominant Yellow fever virus epitope NS4b214-222by combinatorial peptide library screening.
Bovay, A., Zoete, V., Rizkallah, P.J., Beck, K., Delbreil, P., Speiser, D.E., Cole, D.K., Fuertes Marraco, S.A.(2020) Mol Immunol 125: 43-50
- PubMed: 32645549
- DOI: https://doi.org/10.1016/j.molimm.2020.06.025
- Primary Citation of Related Structures:
6SS7, 6SS8, 6SS9, 6SSA - PubMed Abstract:
The CD8 T cell response to the HLA-A2-restricted epitope LLWNGPMAV (LLW) of the non-structural protein 4b of Yellow Fever Virus (YFV) is remarkably immunodominant, highly prevalent and powerful in YFV-vaccinated humans. Here we used a combinatorial peptide library screening in the context of an A2/LLW-specific CD8 T cell clone to identify a superagonist that features a methionine to isoleucine substitution at position 7. Based on in silico modeling, the functional enhancement of this LLW-7I mutation was associated with alterations in the structural dynamics of the peptide in the major histocompatibility complex (pMHC) binding with the T cell receptor (TCR). While the TCR off-rate of LLW-7I pMHC is comparable to the wild type peptide, the rigidity of the 7I peptide seems to confer less entropy loss upon TCR binding. This LLW-7I superagonist is an example of improved functionality in human CD8 T cells associated with optimized ligand rigidity for TCR binding and not with changes in TCR:pMHC off-rate kinetics.
Organizational Affiliation:
Department of Oncology, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
