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Identification of a superagonist variant of the immunodominant Yellow fever virus epitope NS4b214-222 by combinatorial peptide library screening

Bovay, Amandine, Zoete, Vincent, Rizkallah, Pierre J, Beck, Konrad, Delbreil, Philippe, Speiser, Daniel E, Cole, David K and Fuertes Marraco, Silvia A 2020. Identification of a superagonist variant of the immunodominant Yellow fever virus epitope NS4b214-222 by combinatorial peptide library screening. Molecular Immunology 125 , pp. 43-50. 10.1016/j.molimm.2020.06.025

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Dentistry
Medicine
Publisher: Elsevier
ISSN: 0161-5890
Date of First Compliant Deposit: 9 July 2020
Date of Acceptance: 24 June 2020
Last Modified: 31 Aug 2020 16:43
URI: http://orca.cf.ac.uk/id/eprint/133295

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