A cell topography-based mechanism for ligand discrimination by the T cell receptor.
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Ganzinger, Kristina A
Santos, Ana Mafalda
Carr, Alexander R
Chang, Veronica T
Lindsay, Alan E
Davis, Simon J
Proceedings of the National Academy of Sciences of the United States of America
National Academy of Sciences
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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
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.
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
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.
Wellcome Trust (via University of Oxford) (207547/Z/17/Z)
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External DOI: https://doi.org/10.1073/pnas.1817255116
This record's URL: https://www.repository.cam.ac.uk/handle/1810/293127
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