ArticleProceedings of the National Academy of Sciences of the United States of America2019
A cell topography-based mechanism for ligand discrimination by the T cell receptor.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 80 citations in OpenAlex.
- Manufacturing synthetic viscoelastic antigen-presenting cells for immunotherapy.Nature protocols · 2026Review
- Murine T-cell receptor OT-I exhibits imperfect discrimination between foreign and self-antigens.The EMBO journal · 2026Article
- Synergy between membrane topography and domains to control signaling protein localization in mast cells facilitates their activation.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- The Structural Biology of T-Cell Antigen Detection at Close Contacts.Immunological reviews · 2025Review
- The TCR and LCK: foundations for T-cell activation and therapeutic innovation.Frontiers in immunology · 2025Review
- Should Artificial Intelligence Play a Durable Role in Biomedical Research and Practice?International journal of molecular sciences · 2024Review
- Article
- Reliable ligand discrimination in stochastic multistep kinetic proofreading: First passage time vs. product counting strategies.PLoS computational biology · 2024Article
- Membrane organization by tetraspanins and galectins shapes lymphocyte function.Nature reviews. Immunology · 2024Review
- T-cell virtuosity in ''knowing thyself".Frontiers in immunology · 2024Review
- Bayesian metamodeling of early T-cell antigen receptor signaling accounts for its nanoscale activation patterns.Frontiers in immunology · 2024Article
- Antigen perception in T cells by long-term Erk and NFAT signaling dynamics.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Modulation of antigen discrimination by duration of immune contacts in a kinetic proofreading model of T cell activation with extreme statistics.PLoS computational biology · 2023Article
- Antigen discrimination by T cells relies on size-constrained microvillar contact.Nature communications · 2023Article
- Plasma membrane topography governs the 3D dynamic localization of IgM B cell antigen receptor clusters.The EMBO journal · 2023Article
- Pre-organized landscape of T cell surface.Frontiers in immunology · 2023Review
- Recent advances in understanding TCR signaling: a synaptic perspective.Faculty reviews · 2023Review
- T cell microvilli simulations show operation near packing limit and impact on antigen recognition.Biophysical journal · 2022Article
- resPAINT: Accelerating Volumetric Super-Resolution Localisation Microscopy by Active Control of Probe Emission.Angewandte Chemie (International ed. in English) · 2022Article
- resPAINT: Accelerating Volumetric Super-Resolution Localisation Microscopy by Active Control of Probe Emission.Angewandte Chemie (Weinheim an der Bergstrasse, Germany) · 2022Article
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Authors and funding
17 authors at 6 institutions in 4 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.