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

MacLachlan, Bruce J., Dolton, Garry, Papakyriakou, Athanasios, Greenshields-Watson, Alexander, Mason, Georgina H., Schauenburg, Andrea, Besneux, Matthieu, Szomolay, Barbara, Elliott, Tim, Sewell, Andrew K., Gallimore, Awen, Rizkallah, Pierre, Cole, David K. and Godkin, Andrew 2019. Human leukocyte antigen (HLA) class II peptide flanking residues tune the immunogenicity of a human tumor-derived epitope. Journal of Biological Chemistry 294 (52) , pp. 20246-20258. 10.1074/jbc.RA119.009437

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	American Society for Biochemistry and Molecular Biology
ISSN:	0021-9258
Funders:	Wellcome Trust
Date of First Compliant Deposit:	2 January 2020
Date of Acceptance:	18 September 2019
Last Modified:	29 Feb 2020 16:46
URI:	http://orca-mwe.cf.ac.uk/id/eprint/128134

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