Structurally silent peptide anchor modifications allosterically modulate T cell recognition in a receptor-dependent
Angela R Smith1,2, Jesus A Alonso1,2, Cory M Ayres1,2
1Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556.
Summary
Modifying peptide anchors for MHC binding can alter T cell recognition, even without structural changes. These anchor modifications can act as allosteric modulators, impacting T cell receptor binding and immune responses.
Area of Science:
- Immunology
- Molecular Biology
- Structural Biology
Background:
- Class I MHC proteins present peptides, crucial for T cell immunity against pathogens and cancer.
- Engineered peptides with enhanced MHC binding aim to elicit cross-reactive immune responses.
- T cell receptors (TCRs) may perceive modified peptides differently than wild-type (WT) peptides, but the extent is unclear.
Purpose of the Study:
- To investigate how T cell receptors (TCRs) discriminate between anchor-modified and wild-type (WT) peptides.
- To explore the impact of primary anchor modifications on T cell recognition, even without apparent structural changes.
- To elucidate the mechanism by which peptide anchor modifications influence TCR binding and T cell responses.
Main Methods:
- Utilized modified peptides with alterations at primary anchor residues.
- Assessed T cell recognition of modified versus WT peptides across different T cell receptors (TCRs).
- Analyzed the structural and dynamic effects of anchor modifications on MHC-peptide complexes.
Main Results:
- Even minor anchor modifications, without discernible structural impact, significantly altered T cell recognition strength based on the specific TCR.
- TCRs can sense peptide anchor modifications at distant sites, suggesting an allosteric modulation mechanism.
- Anchor residues can function as allosteric modulators influencing TCR binding dynamics.
Conclusions:
- Caution is advised when using and interpreting results from anchor-modified peptides in immunological studies.
- Anchor modifications have implications for predicting tumor neoantigen immunogenicity and understanding immune recognition.
- Further research is needed to understand the dynamic nature of class I MHC proteins and their influence on immune recognition.
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