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

Autor:	Fernandes RA; Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, OX3 9DS Oxford, United Kingdom.; Medical Research Council Human Immunology Unit, John Radcliffe Hospital, University of Oxford, OX3 9DS Oxford, United Kingdom., Ganzinger KA; Department of Chemistry, University of Cambridge, CB2 1EW Cambridge, United Kingdom., Tzou JC; Department of Applied & Computational Mathematics & Statistics, University of Notre Dame, Notre Dame, IN 46556., Jönsson P; Department of Chemistry, University of Cambridge, CB2 1EW Cambridge, United Kingdom., Lee SF; Department of Chemistry, University of Cambridge, CB2 1EW Cambridge, United Kingdom., Palayret M; Department of Chemistry, University of Cambridge, CB2 1EW Cambridge, United Kingdom., Santos AM; Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, OX3 9DS Oxford, United Kingdom.; Medical Research Council Human Immunology Unit, John Radcliffe Hospital, University of Oxford, OX3 9DS Oxford, United Kingdom., Carr AR; Department of Chemistry, University of Cambridge, CB2 1EW Cambridge, United Kingdom., Ponjavic A; Department of Chemistry, University of Cambridge, CB2 1EW Cambridge, United Kingdom., Chang VT; Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, OX3 9DS Oxford, United Kingdom.; Medical Research Council Human Immunology Unit, John Radcliffe Hospital, University of Oxford, OX3 9DS Oxford, United Kingdom., Macleod C; Department of Chemistry, University of Cambridge, CB2 1EW Cambridge, United Kingdom., Lagerholm BC; Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, OX3 9DS Oxford, United Kingdom., Lindsay AE; Mathematics Department, University of British Columbia, Vancouver, BC V6T 1Z2, Canada., Dushek O; Sir William Dunn School of Pathology, University of Oxford, OX1 3RE Oxford, United Kingdom.; Wolfson Centre for Mathematical Biology, University of Oxford, OX1 3RE Oxford, United Kingdom., Tilevik A; School of Bioscience, University of Skövde, 541 28 Skövde, Sweden andreas.tilevik@his.se simon.davis@imm.ox.ac.uk dk10012@cam.ac.uk., Davis SJ; Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, OX3 9DS Oxford, United Kingdom; andreas.tilevik@his.se simon.davis@imm.ox.ac.uk dk10012@cam.ac.uk.; Medical Research Council Human Immunology Unit, John Radcliffe Hospital, University of Oxford, OX3 9DS Oxford, United Kingdom., Klenerman D; Department of Chemistry, University of Cambridge, CB2 1EW Cambridge, United Kingdom; andreas.tilevik@his.se simon.davis@imm.ox.ac.uk dk10012@cam.ac.uk.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2019 Jul 09; Vol. 116 (28), pp. 14002-14010. Date of Electronic Publication: 2019 Jun 20.
DOI:	10.1073/pnas.1817255116
Abstrakt:	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. Competing Interests: The authors declare no conflict of interest. (Copyright © 2019 the Author(s). Published by PNAS.)
Databáze:	MEDLINE
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