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T cells discriminate between groups C1 and C2 HLA-C

View ORCID ProfileMalcolm J. W. Sim, Zachary Stotz, Jinghua Lu, Paul Brennan, Eric O. Long, Peter D. Sun
doi: https://doi.org/10.1101/2021.11.11.468262
Malcolm J. W. Sim
1Structural Immunology Section, Laboratory of Immunogenetics, NIAID, NIH, Rockville, MD 20852
2Molecular & Cellular Immunology Section, Laboratory of Immunogenetics, NIAID, NIH, Rockville, MD 20852
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  • For correspondence: mjwsim@gmail.com psun@niaid.nih.gov
Zachary Stotz
1Structural Immunology Section, Laboratory of Immunogenetics, NIAID, NIH, Rockville, MD 20852
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Jinghua Lu
1Structural Immunology Section, Laboratory of Immunogenetics, NIAID, NIH, Rockville, MD 20852
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Paul Brennan
2Molecular & Cellular Immunology Section, Laboratory of Immunogenetics, NIAID, NIH, Rockville, MD 20852
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Eric O. Long
2Molecular & Cellular Immunology Section, Laboratory of Immunogenetics, NIAID, NIH, Rockville, MD 20852
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Peter D. Sun
1Structural Immunology Section, Laboratory of Immunogenetics, NIAID, NIH, Rockville, MD 20852
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  • For correspondence: mjwsim@gmail.com psun@niaid.nih.gov
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Abstract

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.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license.
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Posted November 13, 2021.
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T cells discriminate between groups C1 and C2 HLA-C
Malcolm J. W. Sim, Zachary Stotz, Jinghua Lu, Paul Brennan, Eric O. Long, Peter D. Sun
bioRxiv 2021.11.11.468262; doi: https://doi.org/10.1101/2021.11.11.468262
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T cells discriminate between groups C1 and C2 HLA-C
Malcolm J. W. Sim, Zachary Stotz, Jinghua Lu, Paul Brennan, Eric O. Long, Peter D. Sun
bioRxiv 2021.11.11.468262; doi: https://doi.org/10.1101/2021.11.11.468262

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