6HBY

HLA class II peptide flanking residues tune the immunogenicity of a human tumor-derived epitope

Summary for 6HBY

• Entry DOI: 10.2210/pdb6hby/pdb
• Descriptor: HLA class II histocompatibility antigen, DR alpha chain, HLA class II histocompatibility antigen, DRB1-1 beta chain, ARRPPLAELAALNLSGSRL 5T4 tumour epitope, ... (7 entities in total)
• Functional Keywords: hla class ii, mhc ii, human, 5t4 tumor epitope, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 92166.05

Authors

MacLachlan, B.,Rizkallah, P.J.,Sewell, A.K.,Cole, D.K.,Godkin, A.J. (deposition date: 2018-08-13, release date: 2019-08-14, Last modification date: 2024-10-23)

Primary citation

MacLachlan, B.J.,Dolton, G.,Papakyriakou, A.,Greenshields-Watson, A.,Mason, G.H.,Schauenburg, A.,Besneux, M.,Szomolay, B.,Elliott, T.,Sewell, A.K.,Gallimore, A.,Rizkallah, P.,Cole, D.K.,Godkin, A.
Human leukocyte antigen (HLA) class II peptide flanking residues tune the immunogenicity of a human tumor-derived epitope.
J.Biol.Chem., 294:20246-20258, 2019

PubMed 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 5T4, 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.

PubMed: 31619516
DOI: 10.1074/jbc.RA119.009437

Experimental method

X-RAY DIFFRACTION (1.95 Å)