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Identification of a superagonist variant of the immunodominant Yellow fever virus epitope NS4b 214-222 by combinatorial peptide library screening

DOI: 10.1016/j.molimm.2020.06.025 DOI Help

Authors: Amandine Bovay (Lausanne University Hospital (CHUV)) , Vincent Zoete (Ludwig Institute for Cancer Research; SIB Swiss Institute of Bioinformatics) , Pierre J. Rizkallah (Cardiff University School of Medicin) , Konrad Beck (Cardiff University School of Dentistry) , Philippe Delbreil (Lausanne University Hospital (CHUV)) , Daniel E. Speiser (Lausanne University Hospital (CHUV)) , David K. Cole (Cardiff University School of Medicine) , Silvia A. Fuertes Marraco (Lausanne University Hospital (CHUV))
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Molecular Immunology , VOL 125 , PAGES 43 - 50

State: Published (Approved)
Published: September 2020

Open Access Open Access

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.

Journal Keywords: Altered peptide ligand; Peptide rigidity; Antigen sensitivity; CD8 T cells; Yellow fever virus

Subject Areas: Biology and Bio-materials


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