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

Accepted version
Peer-reviewed

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Authors

Fernandes, Ricardo A  ORCID logo  https://orcid.org/0000-0001-5343-3334
Ganzinger, Kristina A 
Tzou, Justin C 

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.

Description

Keywords

T cell receptor, dwell time, microvilli, receptor triggering, single-molecule imaging, Animals, Antigen-Presenting Cells, Host-Pathogen Interactions, Humans, Immunity, Innate, Kinetics, Ligands, Lymphocyte Activation, Major Histocompatibility Complex, Microvilli, Models, Theoretical, Peptides, Phosphorylation, Receptors, Antigen, T-Cell, Signal Transduction, Single Molecule Imaging, T-Lymphocytes

Journal Title

Proc Natl Acad Sci U S A

Conference Name

Journal ISSN

0027-8424
1091-6490

Volume Title

116

Publisher

Proceedings of the National Academy of Sciences

Rights

All rights reserved
Sponsorship
Wellcome Trust (via University of Oxford) (207547/Z/17/Z)
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.