T cells discriminate between groups C1 and C2 HLA-C
| Autor: | Zachary Stotz, P Brennan, Eric O. Long, Jinghua Lu, Peter D. Sun, Malcolm J. W. Sim |
|---|---|
| Rok vydání: | 2022 |
| Předmět: |
chemistry.chemical_classification
General Immunology and Microbiology T cell T-Lymphocytes General Neuroscience T-cell receptor Receptors Antigen T-Cell Peptide HLA-C Antigens General Medicine Affinities Molecular biology General Biochemistry Genetics and Molecular Biology Amino acid Natural killer cell Proto-Oncogene Proteins p21(ras) HLA-C medicine.anatomical_structure chemistry medicine Receptor |
| Zdroj: | eLife. 11 |
| ISSN: | 2050-084X |
| DOI: | 10.7554/elife.75670 |
| Popis: | Dimorphic residues at positions 77 and 80 delineate HLA-C allotypes into two groups, C1 and C2, which associate with disease through interactions with C1 and C2-specific natural killer cell receptors. How the C1/C2 dimorphism affects T cell recognition is unknown. Using HLA-C allotypes that differ only by the C1/C2-defining residues, we found that KRAS-G12D neoantigen specific T cell receptors (TCR) discriminated groups C1 and C2 HLA-C, due to effects on peptide presentation and TCR affinity. Structural and functional experiments combined with immunopeptidomics analysis revealed that C1-HLA-C favors smaller amino acids at the peptide C-terminus minus-1 position (pΩ-1), and that larger pΩ-1 residues diminished TCR recognition of C1-HLA-C. After controlling for peptide presentation, TCRs exhibited weaker affinities for C2-HLA-C despite conserved TCR contacts. Thus, the C1/C2 dimorphism impacts peptide presentation and HLA-C restricted T cell responses, with implications in multiple disease contexts including adoptive T cell therapy targeting KRAS-G12D-induced cancers. |
| Databáze: | OpenAIRE |
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