T cells discriminate between groups C1 and C2 HLA-C

Abstract
Data availability
Article and author information
Metrics

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.

The following data sets were generated

1. Sim MJW
2. et al
(2022) KRAS-G12D specific TCR9a in complex with C*05-GADGVGKSL
PDB, 7SU9.

https://www.rcsb.org/structure/7SU9

The following previously published data sets were used

1. Sarkizova S
2. Klaeger S
3. Le PM
4. Li LW
5. Oliveira G
6. Keshishian H
7. Hartigan CH
8. Zhang W
9. Braun DA
10. Ligon KL
11. Bachireddy P
12. Zervantonakis IK
13. Rosenbluth JM
14. Ouspenskaia T
15. Law T
16. Justeson S
17. Stevens J
18. Lane WJ
19. Eisenhaure T
20. Zhang GL
21. Clauser KR
22. Hacohen N
23. Carr SA
24. Wu CJ
25. Keskin DB
(2020) Mono-allelic datasets for: A large peptidome dataset improves HLA class I epitope prediction across most of the human population
MassIVE: Mass Spectrometry Interactive Virtual environment. https://doi.org/10.1038/s41587-019-0322-9.

https://doi.org/doi:10.25345/C5N36Q
(2017) Unveiling the Peptide Motifs of HLA-C and HLA-G from Naturally Presented Peptides and Generation of Binding Prediction Matrices
https://www.ebi.ac.uk/pride/archive/projects/PXD009531.

https://www.jimmunol.org/highwire/filestream/347380/field_highwire_adjunct_files/1/JI_1700938_Supplemental_Table_1.xlsx

Article and author information

Author details

Malcolm JW Sim

Structural Immunology Section, National Institute of Allergy and Infectious Diseases, Rockville, United States

For correspondence
mjwsim@gmail.com

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-3407-9661
Zachary Stotz

Structural Immunology Section, National Institute of Allergy and Infectious Diseases, Rockville, United States

Competing interests
The authors declare that no competing interests exist.
Jinghua Lu

Structural Immunology Section, National Institute of Allergy and Infectious Diseases, Rockville, United States

Competing interests
The authors declare that no competing interests exist.
Paul Brennan

Molecular and Cellular Immunology Section, National Institute of Allergy and Infectious Diseases, Rockville, United States

Competing interests
The authors declare that no competing interests exist.
Eric O Long

Molecular and Cellular Immunology Section, National Institute of Allergy and Infectious Diseases, Rockville, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-7793-3728
Peter D Sun

Structural Immunology Section, National Institute of Allergy and Infectious Diseases, Rockville, United States

For correspondence
PSUN@niaid.nih.gov

Competing interests
The authors declare that no competing interests exist.

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.