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
The following previously published data sets were used

Article and author information

Author details

  1. 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.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3407-9661
  2. 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.
  3. 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.
  4. 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.
  5. 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.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7793-3728
  6. 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.

Reviewing Editor

  1. Chyung-Ru Wang, Northwestern University, United States

Version history

  1. Preprint posted: November 13, 2021 (view preprint)
  2. Received: November 18, 2021
  3. Accepted: May 15, 2022
  4. Accepted Manuscript published: May 19, 2022 (version 1)
  5. Version of Record published: June 8, 2022 (version 2)

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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  1. Malcolm JW Sim
  2. Zachary Stotz
  3. Jinghua Lu
  4. Paul Brennan
  5. Eric O Long
  6. Peter D Sun
(2022)
T cells discriminate between groups C1 and C2 HLA-C
eLife 11:e75670.
https://doi.org/10.7554/eLife.75670

Share this article

https://doi.org/10.7554/eLife.75670

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