RT Journal Article
SR Electronic
T1 T cells discriminate between groups C1 and C2 HLA-C
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.11.11.468262
DO 10.1101/2021.11.11.468262
A1 Sim, Malcolm J. W.
A1 Stotz, Zachary
A1 Lu, Jinghua
A1 Brennan, Paul
A1 Long, Eric O.
A1 Sun, Peter D.
YR 2021
UL http://biorxiv.org/content/early/2021/11/13/2021.11.11.468262.abstract
AB 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 StatementThe authors have declared no competing interest.