Article ; Online: Modification of the HLA-A*24:02 Peptide Binding Pocket Enhances Cognate Peptide-Binding Capacity and Antigen-Specific T Cell Activation.
Journal of immunology (Baltimore, Md. : 1950)
2022 Volume 209, Issue 8, Page(s) 1481–1491
Abstract: 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- ... ...
| Abstract | 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. |
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| MeSH term(s) | Alanine ; Epitopes, T-Lymphocyte ; HLA-A2 Antigen ; HLA-A24 Antigen ; Leucine ; Peptides ; T-Lymphocytes |
| Chemical Substances | Epitopes, T-Lymphocyte ; HLA-A*24:02 antigen ; HLA-A2 Antigen ; HLA-A24 Antigen ; Peptides ; Leucine (GMW67QNF9C) ; Alanine (OF5P57N2ZX) |
| Language | English |
| Publishing date | 2022-09-09 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 3056-9 |
| ISSN | 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381 |
| ISSN (online) | 1550-6606 |
| ISSN | 0022-1767 ; 1048-3233 ; 1047-7381 |
| DOI | 10.4049/jimmunol.2200305 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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