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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 ORCID: https://orcid.org/0000-0002-5375-5533, Elliott, Tim, Sewell, Andrew K. ORCID: https://orcid.org/0000-0003-3194-3135, Gallimore, Awen ORCID: https://orcid.org/0000-0001-6675-7004, Rizkallah, Pierre ORCID: https://orcid.org/0000-0002-9290-0369, Cole, David K. ORCID: https://orcid.org/0000-0003-0028-9396 and Godkin, Andrew ORCID: https://orcid.org/0000-0002-1910-7567 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: 28 May 2023 18:31
URI: https://orca.cardiff.ac.uk/id/eprint/128134

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