T cells discriminate between groups C1 and C2 HLA-C

Dimorphic amino acids 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 diffe...

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Bibliographic Details
Published in:	eLife Vol. 11
Main Authors:	Sim, Malcolm J W, Stotz, Zachary, Lu, Jinghua, Brennan, Paul, Long, Eric O, Sun, Peter D
Format:	Journal Article
Language:	English
Published:	England eLife Sciences Publications Ltd 19-05-2022 eLife Sciences Publications, Ltd
Subjects:	Allotypes Amino acids Antigens C-Terminus C1/C2 Cancer Cell recognition Cell therapy Dimorphism Disease Histocompatibility antigen HLA HLA-C HLA-C Antigens - chemistry Immunology and Inflammation KRAS-G12D Ligands Lymphocytes Lymphocytes T Metastasis Natural killer cells neoantigen Neoantigens Peptides Proto-Oncogene Proteins p21(ras) - genetics Receptors, Antigen, T-Cell Structural Biology and Molecular Biophysics Structure-function relationships T cell receptors T-Lymphocytes TCR neoantigen TCR inflammation C1/C2 HLA-C structural biology molecular biophysics human immunology KRAS-G12D
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Summary:	Dimorphic amino acids 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 (TCRs) discriminated between C1 and C2 presenting the same KRAS-G12D peptides. Structural and functional experiments, and immunopeptidomics analysis revealed that Ser77 in C1 and Asn77 in C2 influence amino acid preference near the peptide C-terminus (pΩ), including the pΩ-1 position, in which C1 favors small and C2 prefers large residues. This resulted in weaker TCR affinity for KRAS-G12D-bound C2-HLA-C despite conserved TCR contacts. Thus, the C1/C2 dimorphism on its own impacts peptide presentation and HLA-C-restricted T cell responses, with implications in disease, including adoptive T cell therapy targeting KRAS-G12D-induced cancers.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 USDOE Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford, Headington, United Kingdom.
ISSN:	2050-084X 2050-084X
DOI:	10.7554/eLife.75670