T cells discriminate between groups C1 and C2 HLA-C

Journal article

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 (TCRs) 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 (pΩ), including the pΩ-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.

Authors: Sim, MJW; Stotz, Z; Lu, J; Brennan, P; Long, EO

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: eLife Sciences Publications
• Journal: eLife
• Volume: 11
• Article number: e75670
• Publication date: 2022-05-19
• Acceptance date: 2022-05-15
• DOI: 10.7554/elife.75670
• EISSN: 2050-084X
• Pmid: 35587797
• Language: English
• Keywords: antigen; T-lymphocytes; proto-oncogene proteins p21(ras); FFR; receptors; HLA-C antigens; T-cell