ArticleeLife2022
Progressive enhancement of kinetic proofreading in T cell antigen discrimination from receptor activation to DAG generation.
Article in eLife, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 32 citations in OpenAlex.
- T cells are blind to the dark mechanics of tumors.Trends open · 2026Review
- Potassium suppresses allosteric activation of ZAP-70-dependent T cell receptor signaling.The Journal of biological chemistry · 2026Article
- Noise as Medicine: The Role of Microbial and Electrical Noise in Restoring Neuroimmune Tolerance Through Stochastic Resonance.NeuroSci · 2025Review
- PmrA Mutations in Drug-ResistantMicroorganisms · 2025Article
- Parallel reactions on a single T cell receptor offer a robust kinetic proofreading mechanism.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Optogenetic engineering for precision cancer immunotherapy.Trends in pharmacological sciences · 2025Review
- Proofreading and single-molecule sensitivity in T cell receptor signaling by condensate nucleation.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- The TCR and LCK: foundations for T-cell activation and therapeutic innovation.Frontiers in immunology · 2025Review
- Flexibility and sensitivity in gene regulation out of equilibrium.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Mechanical force matters in early T cell activation.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Measuring and modeling the dynamics of mitotic error correction.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Design of Crosslinking Antibodies For T-Cell Activation: Experimental and Computational Analysis of PD-1/CD137 Bispecific Agents.The AAPS journal · 2024Article
- Mechanical forces amplify TCR mechanotransduction in T cell activation and function.Applied physics reviews · 2024Review
- Early Chromatin Remodeling Events in Acutely Stimulated CD8The Yale journal of biology and medicine · 2023Article
- Offsetting Low-Affinity Carbohydrate Binding with Covalency to Engage Sugar-Specific Proteins for Tumor-Immune Proximity Induction.ACS central science · 2023Article
- PASCAR: a multiscale framework to explore the design space of constitutive and inducible CAR T cells.Life science alliance · 2023Article
- Proofreading does not result in more reliable ligand discrimination in receptor signaling due to its inherent stochasticity.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Optical sensing and control of T cell signaling pathways.Frontiers in physiology · 2023Review
- Design and engineering of light-sensitive protein switches.Current opinion in structural biology · 2022Review
- Regulating the discriminatory response to antigen by T-cell receptor.Bioscience reports · 2022Review
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
T cells use kinetic proofreading to discriminate antigens by converting small changes in antigen-binding lifetime into large differences in cell activation, but where in the signaling cascade this computation is performed is unknown. Previously, we developed a light-gated immune receptor to probe the role of ligand kinetics in T cell antigen signaling. We found significant kinetic proofreading at the level of the signaling lipid diacylglycerol (DAG) but lacked the ability to determine where the multiple signaling steps required for kinetic discrimination originate in the upstream signaling cascade (Tiseher and Weiner, 2019). Here, we uncover where kinetic proofreading is executed by adapting our optogenetic system for robust activation of early signaling events. We find the strength of kinetic proofreading progressively increases from Zap70 recruitment to LAT clustering to downstream DAG generation. Leveraging the ability of our system to rapidly disengage ligand binding, we also measure slower reset rates for downstream signaling events. These data suggest a distributed kinetic proofreading mechanism, with proofreading steps both at the receptor and at slower resetting downstream signaling complexes that could help balance antigen sensitivity and discrimination.
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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.