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

DOI: 10.1074/jbc.RA119.009437 DOI Help

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

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