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A cell topography-based mechanism for ligand discrimination by the T cell receptor

Fernandes, Ricardo A. ; Ganzinger, Kristina A. ; Tzou, Justin C. ; Jönsson, Peter LU ; Lee, Steven F. ; Palayret, Matthieu ; Santos, Ana Mafalda ; Carr, Alexander R. ; Ponjavic, Aleks and Chang, Veronica T. , et al. (2019) In Proceedings of the National Academy of Sciences 116(28). p.14002-14010
Abstract
The T cell receptor (TCR) initiates the elimination of pathogens and tumors by T cells. To avoid damage to the host, the receptor must be capable of discriminating between wild-type and mutated self and nonself peptide ligands presented by host cells. Exactly how the TCR does this is unknown. In resting T cells, the TCR is largely unphosphorylated due to the dominance of phosphatases over the kinases expressed at the cell surface. However, when agonist peptides are presented to the TCR by major histocompatibility complex proteins expressed by antigen-presenting cells (APCs), very fast receptor triggering, i.e., TCR phosphorylation, occurs. Recent work suggests that this depends on the local exclusion of the phosphatases from regions of... (More)
The T cell receptor (TCR) initiates the elimination of pathogens and tumors by T cells. To avoid damage to the host, the receptor must be capable of discriminating between wild-type and mutated self and nonself peptide ligands presented by host cells. Exactly how the TCR does this is unknown. In resting T cells, the TCR is largely unphosphorylated due to the dominance of phosphatases over the kinases expressed at the cell surface. However, when agonist peptides are presented to the TCR by major histocompatibility complex proteins expressed by antigen-presenting cells (APCs), very fast receptor triggering, i.e., TCR phosphorylation, occurs. Recent work suggests that this depends on the local exclusion of the phosphatases from regions of contact of the T cells with the APCs. Here, we developed and tested a quantitative treatment of receptor triggering reliant only on TCR dwell time in phosphatase-depleted cell contacts constrained in area by cell topography. Using the model and experimentally derived parameters, we found that ligand discrimination likely depends crucially on individual contacts being ∼200 nm in radius, matching the dimensions of the surface protrusions used by T cells to interrogate their targets. The model not only correctly predicted the relative signaling potencies of known agonists and nonagonists but also achieved this in the absence of kinetic proofreading. Our work provides a simple, quantitative, and predictive molecular framework for understanding why TCR triggering is so selective and fast and reveals that, for some receptors, cell topography likely influences signaling outcomes. (Less)
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publishing date
type
Contribution to journal
publication status
published
subject
in
Proceedings of the National Academy of Sciences
volume
116
issue
28
pages
14002 - 14010
publisher
National Academy of Sciences
external identifiers
  • pmid:31221762
  • scopus:85068544091
ISSN
0027-8424
DOI
10.1073/pnas.1817255116
language
English
LU publication?
no
id
65270fbf-ed33-4f9f-bf67-6d062c36d01e
date added to LUP
2019-12-17 07:34:18
date last changed
2022-04-18 19:28:16
@article{65270fbf-ed33-4f9f-bf67-6d062c36d01e,
  abstract     = {{The T cell receptor (TCR) initiates the elimination of pathogens and tumors by T cells. To avoid damage to the host, the receptor must be capable of discriminating between wild-type and mutated self and nonself peptide ligands presented by host cells. Exactly how the TCR does this is unknown. In resting T cells, the TCR is largely unphosphorylated due to the dominance of phosphatases over the kinases expressed at the cell surface. However, when agonist peptides are presented to the TCR by major histocompatibility complex proteins expressed by antigen-presenting cells (APCs), very fast receptor triggering, i.e., TCR phosphorylation, occurs. Recent work suggests that this depends on the local exclusion of the phosphatases from regions of contact of the T cells with the APCs. Here, we developed and tested a quantitative treatment of receptor triggering reliant only on TCR dwell time in phosphatase-depleted cell contacts constrained in area by cell topography. Using the model and experimentally derived parameters, we found that ligand discrimination likely depends crucially on individual contacts being ∼200 nm in radius, matching the dimensions of the surface protrusions used by T cells to interrogate their targets. The model not only correctly predicted the relative signaling potencies of known agonists and nonagonists but also achieved this in the absence of kinetic proofreading. Our work provides a simple, quantitative, and predictive molecular framework for understanding why TCR triggering is so selective and fast and reveals that, for some receptors, cell topography likely influences signaling outcomes.}},
  author       = {{Fernandes, Ricardo A. and Ganzinger, Kristina A. and Tzou, Justin C. and Jönsson, Peter and Lee, Steven F. and Palayret, Matthieu and Santos, Ana Mafalda and Carr, Alexander R. and Ponjavic, Aleks and Chang, Veronica T. and Macleod, Charlotte and Lagerholm, B. Christoffer and Lindsay, Alan E. and Dushek, Omer and Tilevik, Andreas and Davis, Simon J. and Klenerman, David}},
  issn         = {{0027-8424}},
  language     = {{eng}},
  month        = {{05}},
  number       = {{28}},
  pages        = {{14002--14010}},
  publisher    = {{National Academy of Sciences}},
  series       = {{Proceedings of the National Academy of Sciences}},
  title        = {{A cell topography-based mechanism for ligand discrimination by the T cell receptor}},
  url          = {{http://dx.doi.org/10.1073/pnas.1817255116}},
  doi          = {{10.1073/pnas.1817255116}},
  volume       = {{116}},
  year         = {{2019}},
}