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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

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Proceedings of the National Academy of Sciences of the United States of America
|January 20, 2021
PubMed
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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.

Keywords:
MHCT cell receptorallosterybindingmolecular dynamics

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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.