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Updated: May 18, 2026
A TIRF Microscopy Technique for Real-time, Simultaneous Imaging of the TCR and its Associated Signaling Proteins
Published on: March 22, 2012
Proofreading and single-molecule sensitivity in T cell receptor signaling by condensate nucleation
William L White1,2, Hailemikael K Yirdaw1, Ariel J Ben-Sasson2
1Department of Bioengineering, University of Washington, Seattle, WA 98195.
Abstract:
T cells display the remarkable ability to detect single foreign peptides displayed on target cells, while ignoring highly abundant self-peptides. This selectivity has been explained by kinetic proofreading in the T cell receptor (TCR) signaling pathway, which prevents responses to short-lived binding events regardless of their abundance. However, the biochemical mechanisms that drive kinetic proofreading have remained unclear. Here, using computational modeling, we show that these key signaling properties of the TCR pathway can emerge from the dynamics of linker for activation of T cells (LAT) phosphorylation, diffusion, and condensation following TCR-peptide major histocompatibility complex (pMHC) binding. In this model, time delays in LAT condensate nucleation underlie kinetic proofreading, enabling selective signaling responses to high-affinity pMHC ligands. The cooperativity in the nucleation and growth of LAT condensates also provides a mechanism to amplify weak signals from single high-affinity peptides and for condensates to grow with increasing antigen numbers. In contrast to other models, condensate-nucleation proofreading predicts a dependence of signal strength on pMHC spacing at fixed number, a prediction we validated experimentally using a protein scaffold to present pMHCs at defined intervals. Our results suggest that nucleation-condensation proofreading underlies the remarkable antigen detection capabilities of the TCR signaling pathway.
Insights
T cell receptor (TCR) signaling uses kinetic proofreading to distinguish foreign peptides from self-peptides. New research reveals that linker for activation of T cells (LAT) condensate nucleation dynamics drive this crucial selectivity.
Area of Science:
- Immunology
- Cellular Signaling
- Biophysics
Background:
- T cells discriminate between foreign and self-peptides with high sensitivity, a process crucial for immune surveillance.
- Kinetic proofreading is a proposed mechanism for T cell receptor (TCR) signaling selectivity, but its biochemical basis remains elusive.
- Understanding TCR signaling selectivity is key to developing targeted immunotherapies.
Purpose of the Study:
- To elucidate the biochemical mechanisms underlying kinetic proofreading in T cell receptor (TCR) signaling.
- To investigate the role of linker for activation of T cells (LAT) phosphorylation, diffusion, and condensation in TCR signal processing.
- To model and experimentally validate a novel kinetic proofreading mechanism based on LAT condensate nucleation.
Main Methods:
- Computational modeling of TCR-pMHC interactions and LAT dynamics.
- Simulating LAT phosphorylation, diffusion, and condensate formation kinetics.
- Experimental validation using protein scaffolds to control peptide-MHC (pMHC) spacing.
Main Results:
- A computational model demonstrated that LAT condensate nucleation dynamics can explain TCR signaling selectivity.
- Time delays in LAT condensate nucleation were identified as the basis for kinetic proofreading.
- The model predicted and experiments confirmed that pMHC spacing influences signal strength, supporting condensate-nucleation proofreading.
Conclusions:
- Nucleation-condensation of LAT provides a biochemical mechanism for kinetic proofreading in TCR signaling.
- This mechanism enables T cells to selectively respond to high-affinity peptides and amplify weak signals.
- The findings offer new insights into the exquisite antigen detection capabilities of the T cell receptor signaling pathway.
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