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Human leukocyte antigen (HLA) class II peptide flanking residues tune the immunogenicity of a human tumor-derived epitope

Authors :
Andrea J. A. Schauenburg
Matthieu Besneux
Bruce J. MacLachlan
David K. Cole
Barbara Szomolay
Tim Elliott
Awen Gallimore
Garry Dolton
Andrew K. Sewell
Alexander Greenshields-Watson
Athanasios Papakyriakou
Pierre J. Rizkallah
Andrew James Godkin
Georgina H. Mason
Source :
The Journal of Biological Chemistry
Publication Year :
2019

Abstract

CD4+ T-cells recognize peptide antigens, in the context of human leukocyte antigen (HLA) class II molecules (HLA-II), which through peptide-flanking residues (PFRs) can extend beyond the limits of the HLA binding. The role of the PFRs during antigen recognition is not fully understood; however, recent studies have indicated that these regions can influence T-cell receptor (TCR) affinity and pHLA-II stability. Here, using various biochemical approaches including peptide sensitivity ELISA and ELISpot assays, peptide-binding assays and HLA-II tetramer staining, we focused on CD4+ T-cell responses against a tumor antigen, 5T4 oncofetal trophoblast glycoprotein (5T4), which have been associated with improved control of colorectal cancer. Despite their weak TCR-binding affinity, we found that anti-5T4 CD4+ T-cells are polyfunctional and that their PFRs are essential for TCR recognition of the core bound nonamer. The high-resolution (1.95 Å) crystal structure of HLA-DR1 presenting the immunodominant 20-mer peptide 5T4111-130, combined with molecular dynamic simulations, revealed how PFRs explore the HLA-proximal space to contribute to antigen reactivity. These findings advance our understanding of what constitutes an HLA-II epitope and indicate that PFRs can tune weak affinity TCR-pHLA-II interactions.

Details

Language :
English
ISSN :
00219258
Database :
OpenAIRE
Journal :
The Journal of Biological Chemistry
Accession number :
edsair.doi.dedup.....c3c61cec5cc9e6c62a6e657e5257cb79