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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
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

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
Diamond Keywords: Yellow Fever; Viruses
Subject Areas:
Biology and Bio-materials
Instruments:
I03-Macromolecular Crystallography
Added On:
14/07/2020 10:52
Documents:
1-s2.0-S016158902030403X-main.pdf
Discipline Tags:
Pathogens
Infectious Diseases
Disease in the Developing World
Health & Wellbeing
Life Sciences & Biotech
Technical Tags:
Diffraction
Macromolecular Crystallography (MX)