Naturally processed non-canonical HLA-A*02:01 presented peptides

Area of Science:

• Immunology
• Structural Biology
• Molecular Biology

Background:

• Human Leukocyte Antigen (HLA) class I molecules typically present peptides (p) of 8-11 amino acids (aa).
• Longer peptides (>11 aa) presentation is increasingly reported, predominantly by HLA-B alleles.

Purpose of the Study:

• To characterize lengthy peptides (>11 aa) presented by HLA-A*02:01, HLA-B*0702, and HLA-B*4402.
• To investigate the binding, stability, structure, and immunogenicity of 15-mer peptides presented by HLA-A*02:01.

Main Methods:

• Analysis of 15-mer peptides presented by HLA-A*02:01.
• HLA folding and thermal stability assays to confirm peptide-HLA class I (pHLA-I) formation.
• X-ray crystallography to determine the structures of peptide-HLA-A*02:01 complexes.
• T-cell recognition assays.

Main Results:

• 15-mer peptides presented by HLA-A*02:01 demonstrated binding affinity and stability comparable to canonical length peptides (8-11 aa).
• Structural analysis revealed that 15-mer peptides adopt distinct super-bulged conformations when bound to HLA-A*02:01.
• T-cells recognized these 15-mer peptides in the context of HLA-A*02:01, confirming their immunogenic nature.

Conclusions:

• Lengthy peptides are not exclusively presented by HLA-B alleles but can also bind to the common HLA-A*02:01 molecule.
• These longer epitopes, when bound to HLA-A*02:01, adopt unique conformations and are immunogenic, expanding the known repertoire of HLA class I ligands.
• The findings highlight the significant role of longer peptides in T-cell immunity beyond the canonical length presentation.