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A cell topography-based mechanism for ligand discrimination by the T cell receptor
Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, United Kingdom / Medical Research Council Human Immunology Unit, John Radcliffe Hospital, University of Oxford, United Kingdom / Department of Molecular and Cellular Physiology, Department of Structural Biology, Stanford University, United States.
Department of Chemistry, University of Cambridge, United Kingdom / Living Matter Department, Physics of Cellular Interactions Group, AMOLF, Amsterdam, Netherlands.
Department of Applied and Computational Mathematics and Statistics, University of Notre Dame, United States.
Department of Chemistry, University of Cambridge, United Kingdom / Department of Chemistry, Lund University, Sweden.
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2019 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, no 28, p. 14002-14010Article in journal (Refereed) Published
Abstract [en]

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. 

Place, publisher, year, edition, pages
National Academy of Sciences , 2019. Vol. 116, no 28, p. 14002-14010
Keywords [en]
Dwell time, Microvilli, Receptor triggering, Single-molecule imaging, T cell receptor
National Category
Immunology
Research subject
Infection Biology
Identifiers
URN: urn:nbn:se:his:diva-17471DOI: 10.1073/pnas.1817255116ISI: 000474535700052PubMedID: 31221762Scopus ID: 2-s2.0-85068544091OAI: oai:DiVA.org:his-17471DiVA, id: diva2:1338363
Available from: 2019-07-22 Created: 2019-07-22 Last updated: 2019-07-26Bibliographically approved

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