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Human leukocyte antigen (HLA) class II peptide flanking residues tune the immunogenicity of a human tumor-derived epitope
- Source :
- The Journal of Biological Chemistry
- Publication Year :
- 2019
-
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.
- Subjects :
- 0301 basic medicine
CD4-Positive T-Lymphocytes
Antigen presentation
Immunology
Context (language use)
Human leukocyte antigen
peptide flanking residues
Molecular Dynamics Simulation
Crystallography, X-Ray
Biochemistry
T-cell biology
Epitope
structure-function
Protein Structure, Secondary
03 medical and health sciences
Epitopes
Antigen
Humans
tumor immunology
Amino Acid Sequence
crystallography
Molecular Biology
Binding Sites
Membrane Glycoproteins
030102 biochemistry & molecular biology
Chemistry
Immunogenicity
T-cell receptor
HLA-DR1 Antigen
Cell Biology
Molecular biology
Tumor antigen
molecular dynamics
antigen recognition
Protein Structure, Tertiary
antigen presentation
030104 developmental biology
Colorectal Neoplasms
Peptides
Protein Binding
Subjects
Details
- Language :
- English
- ISSN :
- 00219258
- Database :
- OpenAIRE
- Journal :
- The Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....c3c61cec5cc9e6c62a6e657e5257cb79