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Human leukocyte antigen (HLA) class II peptide flanking residues tune the immunogenicity of a human tumor-derived epitope
Authors:
Bruce J.
Maclachlan
(Cardiff University)
,
Garry
Dolton
(Cardiff University)
,
Athanasios
Papakyriakou
(National Centre for Scientific Research, Greece)
,
Alexander
Greenshields-watson
(Cardiff University)
,
Georgina H.
Mason
(Cardiff University)
,
Andrea
Schauenburg
(Cardiff University)
,
Matthieu
Besneux
(Cardiff University)
,
Barbara
Szomolay
(Cardiff University)
,
Tim
Elliott
(Unviersity of Southampton)
,
Andrew K.
Sewell
(Cardiff University School of Medicine)
,
Awen
Gallimore
(Cardiff University)
,
Pierre
Rizkallah
(Cardiff University)
,
David K.
Cole
(Cardiff University)
,
Andrew
Godkin
(Cardiff University)
Co-authored by industrial partner:
No
Type:
Journal Paper
Journal:
Journal Of Biological Chemistry
State:
Published (Approved)
Published:
October 2019
Diamond Proposal Number(s):
10462
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 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 T-cell receptor (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.
Journal Keywords: peptide flanking residues; antigen recognition; T-cell biology; tumor immunology; antigen presentation; structure-function; molecular dynamics; crystallography
Subject Areas:
Biology and Bio-materials
Instruments:
I02-Macromolecular Crystallography