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

Amandine Bovay; Vincent Zoete; Pierre J Rizkallah; Konrad Beck; Philippe Delbreil; Daniel E Speiser; David K Cole; Silvia A Fuertes Marraco

doi:10.1016/j.molimm.2020.06.025

Identification of a superagonist variant of the immunodominant Yellow fever virus epitope NS4b _214-222 by combinatorial peptide library screening

Mol Immunol. 2020 Sep:125:43-50. doi: 10.1016/j.molimm.2020.06.025. Epub 2020 Jul 6.

Authors

Amandine Bovay¹, Vincent Zoete², Pierre J Rizkallah³, Konrad Beck⁴, Philippe Delbreil¹, Daniel E Speiser¹, David K Cole³, Silvia A Fuertes Marraco⁵

Affiliations

¹ Department of Oncology, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
² Department of oncology CHUV-UNIL, Ludwig Institute for Cancer Research, Epalinges, Switzerland; SIB Swiss Institute of Bioinformatics, Molecular Modeling Group, Lausanne, Switzerland.
³ Division of Infection and Immunity and Systems Immunity Research Institute, Cardiff University School of Medicine, Heath Park, Cardiff, United Kingdom.
⁴ Cardiff University School of Dentistry, Heath Park, Cardiff, United Kingdom.
⁵ Department of Oncology, Lausanne University Hospital (CHUV), Lausanne, Switzerland. Electronic address: [email protected].

PMID: 32645549
DOI: 10.1016/j.molimm.2020.06.025

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.

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

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

CD8-Positive T-Lymphocytes / immunology*
Epitopes, T-Lymphocyte / chemistry
Epitopes, T-Lymphocyte / immunology
HLA-A2 Antigen / chemistry
HLA-A2 Antigen / immunology
Humans
Immunodominant Epitopes / chemistry
Immunodominant Epitopes / immunology*
Models, Molecular
Mutation
Peptide Library
Protein Binding / immunology
Receptors, Antigen, T-Cell / chemistry
Receptors, Antigen, T-Cell / immunology*
Viral Nonstructural Proteins / immunology*
Yellow fever virus / immunology*

Substances

Epitopes, T-Lymphocyte
HLA-A2 Antigen
Immunodominant Epitopes
Peptide Library
Receptors, Antigen, T-Cell
Viral Nonstructural Proteins