FIRST PASSAGE TIMES TO T CELL ACTIVATION.

Area of Science:

• Immunology
• Computational Biology
• Systems Biology

Background:

• Adaptive immune responses depend on T cell activation by antigen-presenting cells (APCs) within lymph nodes.
• T cells encounter both cognate (antigen-presenting) and non-cognate APCs, alongside risks of degradation and lymph node exit.
• Understanding T cell-APC interactions is crucial for deciphering immune response initiation.

Purpose of the Study:

• To develop a quantitative framework for T cell activation within the lymph node.
• To analyze the probability and timing of T cell activation considering various biological factors.
• To investigate the role of kinetic proofreading in enhancing T cell specificity.

Main Methods:

• A stochastic model using a multistage Markov chain to represent T cell-APC interactions.
• Integration of T cell diffusion, APC abundance, T cell death, and lymph node exit into a quantitative framework.
• Analysis of a system of partial differential equations under specific boundary conditions, employing first-passage time theory.

Main Results:

• Calculated the probability of successful T cell activation in the presence of interfering factors.
• Determined the mean first-passage time to T cell activation.
• Demonstrated that kinetic proofreading significantly enhances specificity towards cognate APCs.

Conclusions:

• The developed model provides fundamental insights into the onset of adaptive immunity.
• Kinetic proofreading is identified as a key mechanism for improving T cell recognition specificity.
• The framework allows for the estimation of spatio-temporal parameters influencing T cell activation.