T cells discriminate between groups C1 and C2 HLA-C
- National Institute of Allergy and Infectious Diseases, United States
Abstract
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 (TCR) 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 (pW), including the pW-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.
Data availability
Diffraction data have been deposited in PDB under the accession code 7SU9.
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Mono-allelic datasets for: A large peptidome dataset improves HLA class I epitope prediction across most of the human populationMassIVE: Mass Spectrometry Interactive Virtual environment. https://doi.org/10.1038/s41587-019-0322-9.
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Unveiling the Peptide Motifs of HLA-C and HLA-G from Naturally Presented Peptides and Generation of Binding Prediction Matriceshttps://www.ebi.ac.uk/pride/archive/projects/PXD009531.
Article and author information
Author details
Funding
NIAID Division of Intramural Research Funding (AI000697)
- Peter D Sun
NIAID Division of Intramural Research Funding (AI000525)
- Eric O Long
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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T cells discriminate between groups C1 and C2 HLA-C
eLife 11:e75670.
https://doi.org/10.7554/eLife.75670
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