Structurally silent peptide anchor modifications allosterically modulate T cell recognition in a receptor-dependent manner
Abstract
Presentation of peptides by class I MHC proteins underlies T cell immune responses to pathogens and cancer. The association between peptide binding affinity and immunogenicity has led to the engineering of modified peptides with improved MHC binding, with the hope that these peptides would be useful for eliciting cross-reactive immune responses directed toward their weak binding, unmodified counterparts. Increasing evidence, however, indicates that T cell receptors (TCRs) can perceive such anchor-modified peptides differently than wild-type (WT) peptides, although the scope of discrimination is unclear. We show here that even modifications at primary anchors that have no discernible structural impact can lead to substantially stronger or weaker T cell recognition depending on the TCR. Surprisingly, the effect of peptide anchor modification can be sensed by a TCR at regions distant from the site of modification, indicating a through-protein mechanism in which the anchor residue serves as an allosteric modulator for TCR binding. Our findings emphasize caution in the use and interpretation of results from anchor-modified peptides and have implications for how anchor modifications are accounted for in other circumstances, such as predicting the immunogenicity of tumor neoantigens. Our data also highlight an important need to better understand the highly tunable dynamicmore »
- Authors:
-
[1]
- Univ. of Notre Dame, IN (United States)
- Nevada State College, Henderson, NV (United States)
- Publication Date:
- Research Org.:
- Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- National Institute of General Medical Sciences (NIGMS); National Institutes of Health (NIH); Walther Cancer Foundation; National Cancer Institute (NCI); USDOE Office of Science (SC), Basic Energy Sciences (BES)
- OSTI Identifier:
- 1763085
- Grant/Contract Number:
- R35GM118166; S10RR25528; S10RR028976; W-31-109-Eng-38
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Proceedings of the National Academy of Sciences of the United States of America
- Additional Journal Information:
- Journal Volume: 118; Journal Issue: 4; Journal ID: ISSN 0027-8424
- Publisher:
- National Academy of Sciences
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 60 APPLIED LIFE SCIENCES; T cell receptor; MHC; binding; allostery; molecular dynamics
Citation Formats
Smith, Angela R., Alonso, Jesus A., Ayres, Cory M., Singh, Nishant K., Hellman, Lance M., and Baker, Brian M. Structurally silent peptide anchor modifications allosterically modulate T cell recognition in a receptor-dependent manner. United States: N. p., 2021.
Web. doi:10.1073/pnas.2018125118.
Smith, Angela R., Alonso, Jesus A., Ayres, Cory M., Singh, Nishant K., Hellman, Lance M., & Baker, Brian M. Structurally silent peptide anchor modifications allosterically modulate T cell recognition in a receptor-dependent manner. United States. https://doi.org/10.1073/pnas.2018125118
Smith, Angela R., Alonso, Jesus A., Ayres, Cory M., Singh, Nishant K., Hellman, Lance M., and Baker, Brian M. Tue .
"Structurally silent peptide anchor modifications allosterically modulate T cell recognition in a receptor-dependent manner". United States. https://doi.org/10.1073/pnas.2018125118. https://www.osti.gov/servlets/purl/1763085.
@article{osti_1763085,
title = {Structurally silent peptide anchor modifications allosterically modulate T cell recognition in a receptor-dependent manner},
author = {Smith, Angela R. and Alonso, Jesus A. and Ayres, Cory M. and Singh, Nishant K. and Hellman, Lance M. and Baker, Brian M.},
abstractNote = {Presentation of peptides by class I MHC proteins underlies T cell immune responses to pathogens and cancer. The association between peptide binding affinity and immunogenicity has led to the engineering of modified peptides with improved MHC binding, with the hope that these peptides would be useful for eliciting cross-reactive immune responses directed toward their weak binding, unmodified counterparts. Increasing evidence, however, indicates that T cell receptors (TCRs) can perceive such anchor-modified peptides differently than wild-type (WT) peptides, although the scope of discrimination is unclear. We show here that even modifications at primary anchors that have no discernible structural impact can lead to substantially stronger or weaker T cell recognition depending on the TCR. Surprisingly, the effect of peptide anchor modification can be sensed by a TCR at regions distant from the site of modification, indicating a through-protein mechanism in which the anchor residue serves as an allosteric modulator for TCR binding. Our findings emphasize caution in the use and interpretation of results from anchor-modified peptides and have implications for how anchor modifications are accounted for in other circumstances, such as predicting the immunogenicity of tumor neoantigens. Our data also highlight an important need to better understand the highly tunable dynamic nature of class I MHC proteins and the impact this has on various forms of immune recognition.},
doi = {10.1073/pnas.2018125118},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 4,
volume = 118,
place = {United States},
year = {Tue Jan 26 00:00:00 EST 2021},
month = {Tue Jan 26 00:00:00 EST 2021}
}
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