Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 294, Issue 52, Pages 20246-20258Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA119.009437
Keywords
T-cell biology; tumor immunology; antigen presentation; molecular dynamics; crystallography; structure-function; antigen recognition; peptide flanking residues
Categories
Funding
- Cancer Research UK (CRUK) studentship
- Wales Cancer Research Centre
- EU Horizon2020 Marie Sklodowska-Curie fellowship DynOMIS Grant [703530]
- CRUK
- Cancer Research Wales
- Wellcome Trust
- Marie Curie Actions (MSCA) [703530] Funding Source: Marie Curie Actions (MSCA)
Ask authors/readers for more resources
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 ?) crystal structure of HLA-DR1 presenting the immunodominant 20-mer peptide 5T4(111?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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available