A cell topography-based mechanism for ligand discrimination by the T cell receptor.
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Authors
Ganzinger, Kristina A
Santos, Ana Mafalda
Carr, Alexander R
Chang, Veronica T
Macleod, Charlotte
Lindsay, Alan E
Tilevik, Andreas
Davis, Simon J
Publication Date
2019-07Journal Title
Proceedings of the National Academy of Sciences of the United States of America
ISSN
0027-8424
Publisher
National Academy of Sciences
Volume
116
Issue
28
Pages
14002-14010
Language
eng
Type
Article
This Version
AM
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Fernandes, R. A., Ganzinger, K. A., Tzou, J. C., Jönsson, P., Lee, S., Palayret, M., Santos, A. M., et al. (2019). A cell topography-based mechanism for ligand discrimination by the T cell receptor.. Proceedings of the National Academy of Sciences of the United States of America, 116 (28), 14002-14010. https://doi.org/10.1073/pnas.1817255116
Abstract
The T-cell receptor (TCR) initiates the elimination of pathogens and tumors by T cells. In order to avoid damage to the host, the receptor must be capable of discriminating between wild-type and mutated, self and non-self 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 upon 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 non-agonists but 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.
Keywords
Antigen-Presenting Cells, T-Lymphocytes, Microvilli, Animals, Humans, Peptides, Receptors, Antigen, T-Cell, Ligands, Lymphocyte Activation, Signal Transduction, Major Histocompatibility Complex, Phosphorylation, Kinetics, Models, Theoretical, Host-Pathogen Interactions, Immunity, Innate, Single Molecule Imaging
Sponsorship
This work was funded by The Wellcome Trust, the UK Medical Research Council, the UK Biotechnology and Biological Sciences Research Council and Cancer Research UK. We thank the Wolfson Imaging Centre, University of Oxford, for access to their microscope facility. We would like to thank the Wellcome Trust for the Sir Henry Dale Fellowship of R.A.F. (WT101609MA), the Royal Society for the University Research Fellowship of S.F.L. (UF120277) and acknowledge a GSK Professorship (D.K.). We are also grateful to Doug Tischer (UCSF, US) and Muaz Rushdi (Georgia Tech, US) for their critical comments on the manuscript.
Funder references
Wellcome Trust (via University of Oxford) (207547/Z/17/Z)
Embargo Lift Date
2022-05-24
Identifiers
External DOI: https://doi.org/10.1073/pnas.1817255116
This record's URL: https://www.repository.cam.ac.uk/handle/1810/293127
Rights
All rights reserved