T-cell activation: A queuing theory analysis at low agonist density.

Area of Science:

• Immunology
• Theoretical Biology
• Biophysics

Background:

• T-cell receptor (TCR) signaling is crucial for adaptive immunity.
• Understanding TCR activation thresholds and their impact on T-cell function is essential.
• Queuing theory offers a framework to model dynamic biological processes like TCR signaling.

Purpose of the Study:

• To develop and analyze a linear triggering model for TCR activation using queuing theory.
• To evaluate the specificity and sensitivity of different TCR activation criteria.
• To investigate the robustness of these criteria under parameter variations and the role of signal integration.

Main Methods:

• Development of a simple linear triggering model for TCRs based on queuing theory.
• Fitting the model to four experimental activation criteria: calcium spike, cytotoxicity, synapse formation, and cytokine secretion.
• Robustness analysis considering parameter variations and stochasticity.
• Analysis of signal integration over extended time periods.

Main Results:

• Specificity improves with longer detection time windows, saturating on the timescale of TCR downregulation.
• The calcium spike (30s) shows low specificity but high sensitivity to single-peptide MHC ligands.
• The cytokine threshold (1h) can distinguish ligands with 30% variation in complex lifetime.
• Signal integration over hours effectively controls parameter noise and enhances discrimination.
• Discrimination characteristics are governed by TCR signal cascade kinetics (kinetic proofreading).

Conclusions:

• T-cell activation relies on a combination of threshold mechanisms and signal integration.
• Signal integration over hours improves T-cell responsiveness to low ligand density and specificity to agonist quality.
• Multiple thresholds likely coordinate stable contact interface formation for efficient signal integration.