HLA micropolymorphisms confine neoantigen conformational adaptability and guide T cell receptor selectivity
Jiaqi Ma1, Cory M Ayres1, Chad A Brambley1
1Harper Cancer Research Institute and the Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46656.
Summary
Micropolymorphisms in human leukocyte antigen (HLA) proteins alter neoantigen conformation, impacting T cell receptor (TCR) binding. This highlights the importance of high-resolution HLA typing for understanding cellular immunity and developing immunotherapies.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- T cell receptor (TCR) recognition is restricted by highly polymorphic major histocompatibility complex (MHC) proteins.
- The impact of minor MHC (micropolymorphisms) on immune recognition remains unclear.
- Previous work showed TCRs specific for a PIK3CA neoantigen presented by HLA-A*03:01 could not recognize it when presented by HLA-A*03:02.
Purpose of the Study:
- To elucidate the mechanism by which micropolymorphisms in closely related HLA-A3 superfamily members govern TCR specificity.
- To understand how structural variations affect neoantigen presentation and recognition.
Main Methods:
- Comparative analysis of TCR recognition of neoantigens presented by HLA-A*03:01 and HLA-A*03:02.
- Investigation of peptide binding, static structures, and conformational ensembles of neoantigen/HLA complexes.
- Analysis of covarying polymorphisms and their interaction networks.
Main Results:
- Two micropolymorphisms distinguishing HLA-A*03:02 from HLA-A*03:01 prevent TCR binding.
- These polymorphisms do not alter peptide binding or static structures but affect the neoantigen's conformational ensemble.
- The neoantigen fails to adopt a binding-permissive state due to altered conformational adaptability controlled by a cross-groove network of interactions.
Conclusions:
- Polymorphism-dependent conformational adaptability is a key feature of class I MHC proteins.
- This adaptability diversifies epitopes and influences TCR-antigen discrimination.
- High-resolution HLA typing is crucial for immunological studies and antigen-specific immunotherapy.
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