HLA micropolymorphisms confine neoantigen conformational adaptability and guide T cell receptor selectivity

Area of Science:

• Immunology
• Molecular Biology
• Structural Biology

Background:

• T cell receptor (TCR) recognition is restricted by polymorphic major histocompatibility complex (MHC) proteins.
• The impact of minor MHC polymorphisms (micropolymorphisms) on immune recognition remains unclear.

Purpose of the Study:

• To investigate how micropolymorphisms in closely related HLA-A3 superfamily members influence TCR specificity.
• To elucidate the molecular mechanism by which HLA micropolymorphisms affect neoantigen presentation and recognition.

Main Methods:

• Comparative analysis of TCR recognition for a PIK3CA neoantigen presented by HLA-A*03:01 versus HLA-A*03:02.
• Investigation of peptide/HLA complex dynamics and conformational ensembles.
• Analysis of co-varying polymorphisms and interaction networks within MHC molecules.

Main Results:

• Micropolymorphisms between HLA-A*03:01 and HLA-A*03:02 prevent TCR recognition of a specific neoantigen.
• These polymorphisms alter the neoantigen's conformational ensemble, hindering TCR binding.
• Static crystal structures of the peptide/HLA complexes are indistinguishable, underscoring the role of dynamics.

Conclusions:

• HLA micropolymorphisms fine-tune TCR specificity by modulating peptide presentation dynamics.
• A cross-groove network of interactions controls peptide/HLA conformational adaptability.
• High-resolution HLA typing is crucial for immunology and antigen-specific immunotherapy.