T cells discriminate between groups C1 and C2 HLA-C

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Human Leukocyte Antigen C (HLA-C) allotypes are grouped into C1 and C2 based on dimorphic amino acids at positions 77 and 80.
• These groups are known to interact with specific natural killer cell receptors and are associated with various diseases.
• The effect of the C1/C2 dimorphism on T cell recognition remains largely unexplored.

Purpose of the Study:

• To investigate how the C1/C2 dimorphism in HLA-C molecules influences T cell receptor (TCR) recognition.
• To determine the impact of this dimorphism on the presentation of KRAS-G12D neoantigens.
• To understand the implications for T cell responses in diseases, including cancer.

Main Methods:

• Utilized HLA-C allotypes differing solely at C1/C2-defining residues.
• Employed KRAS-G12D neoantigen-specific T cell receptors (TCRs) for recognition studies.
• Conducted structural and functional experiments, alongside immunopeptidomics analysis.

Main Results:

• TCRs demonstrated discrimination between C1 and C2 allotypes presenting the same KRAS-G12D peptides.
• The C1/C2 dimorphism, specifically residue 77 (Serine in C1, Asparagine in C2), influences peptide C-terminal amino acid preference.
• C1 favors small residues at pΩ-1, while C2 prefers larger residues, leading to reduced TCR affinity for C2-HLA-C complexes.

Conclusions:

• The C1/C2 dimorphism intrinsically affects peptide presentation by HLA-C molecules.
• This dimorphism significantly impacts HLA-C-restricted T cell responses, even with conserved TCR contacts.
• Findings have implications for understanding disease associations and developing targeted adoptive T cell therapies for KRAS-G12D-induced cancers.