期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 290, 期 5, 页码 2593-2603出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M114.607028
关键词
Crystallography; Immunology; Mass Spectrometry (MS); Peptide Conformation; Peptides; HLA-A*02:01; Human Leukocyte Antigen Class I; T-cell Immunity; Peptidomics
资金
- Landsteiner Foundation for Blood Transfusion Research [LSBR0713]
- Australian Research Council
- National Health and Medical Research Council of Australia
- National Health and Medical Research Council of Australia (NHMRC) Australia Fellowship
- Australian Research Council [FT120100416]
- Australian Research Council [FT120100416] Funding Source: Australian Research Council
Background: The impact of long epitopes on T-cell immunity remains unclear. Results: We identified and characterized 15-mer epitopes restricted to HLA-A*02:01. Conclusion: HLA-A*02:01, in addition to the HLA-B family, can bind long epitopes that represent new antigenic targets for CD8(+) T-cells. Significance: The characterization of 15-mer epitopes restricted to HLA-A*02:01 expands our knowledge of the HLA-ligandome. Human leukocyte antigen (HLA) class I molecules generally present peptides (p) of 8 to 11 amino acids (aa) in length. Although an increasing number of examples with lengthy (>11 aa) peptides, presented mostly by HLA-B alleles, have been reported. Here we characterize HLA-A*02:01 restricted, in addition to the HLA-B*0702 and HLA-B*4402 restricted, lengthy peptides (>11 aa) arising from the B-cell ligandome. We analyzed a number of 15-mer peptides presented by HLA-A*02:01, and confirmed pHLA-I formation by HLA folding and thermal stability assays. Surprisingly the binding affinity and stability of the 15-mer epitopes in complex with HLA-A*02:01 were comparable with the values observed for canonical length (8 to 11 aa) HLA-A*02:01-restricted peptides. We solved the structures of two 15-mer epitopes in complex with HLA-A*02:01, within which the peptides adopted distinct super-bulged conformations. Moreover, we demonstrate that T-cells can recognize the 15-mer peptides in the context of HLA-A*02:01, indicating that these 15-mer peptides represent immunogenic ligands. Collectively, our data expand our understanding of longer epitopes in the context of HLA-I, highlighting that they are not limited to the HLA-B family, but can bind the ubiquitous HLA-A*02:01 molecule, and play an important role in T-cell immunity.
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