Modification of the HLA-A*24:02 Peptide Binding Pocket Enhances Cognate Peptide-Binding Capacity and Antigen-Specific T Cell Activation
| العنوان: | Modification of the HLA-A*24:02 Peptide Binding Pocket Enhances Cognate Peptide-Binding Capacity and Antigen-Specific T Cell Activation |
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| المؤلفون: | Kenji Murata, Dalam Ly, Hiroshi Saijo, Yukiko Matsunaga, Kenji Sugata, Fumie Ihara, Daisuke Oryoji, Yota Ohashi, Kayoko Saso, Chung-Hsi Wang, Evey Y.F. Zheng, Brian D. Burt, Marcus O. Butler, Naoto Hirano |
| المصدر: | The Journal of Immunology. 209:1481-1491 |
| بيانات النشر: | The American Association of Immunologists, 2022. |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | Alanine, Leucine, T-Lymphocytes, HLA-A2 Antigen, Immunology, Epitopes, T-Lymphocyte, HLA-A24 Antigen, Immunology and Allergy, Peptides |
| الوصف: | The immunogenicity of a T cell Ag is correlated with the ability of its antigenic epitope to bind HLA and be stably presented to T cells. This presents a challenge for the development of effective cancer immunotherapies, as many self-derived tumor-associated epitopes elicit weak T cell responses, in part due to weak binding affinity to HLA. Traditional methods to increase peptide–HLA binding affinity involve modifying the peptide to reflect HLA allele binding preferences. Using a different approach, we sought to analyze whether the immunogenicity of wild-type peptides could be altered through modification of the HLA binding pocket. After analyzing HLA class I peptide binding pocket alignments, we identified an alanine 81 to leucine (A81L) modification within the F binding pocket of HLA-A*24:02 that was found to heighten the ability of artificial APCs to retain and present HLA-A*24:02–restricted peptides, resulting in increased T cell responses while retaining Ag specificity. This modification led to increased peptide exchange efficiencies for enhanced detection of low-avidity T cells and, when expressed on artificial APCs, resulted in greater expansion of Ag-specific T cells from melanoma-derived tumor-infiltrating lymphocytes. Our study provides an example of how modifications to the HLA binding pocket can enhance wild-type cognate peptide presentation to heighten T cell activation. |
| تدمد: | 1550-6606 0022-1767 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::13a8258c3ce63974dc70958cc51deda9 https://doi.org/10.4049/jimmunol.2200305 |
| رقم الأكسشن: | edsair.doi.dedup.....13a8258c3ce63974dc70958cc51deda9 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15506606 00221767 |
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