Cellular-level versus receptor-level response threshold hierarchies in T-cell activation

Area of Science:

• Immunology
• Cellular Biology
• Biophysics

Background:

• T-cell receptor (TCR) engagement with peptide-MHC (pMHC) ligands triggers diverse cellular responses.
• The hierarchy of stimulation thresholds for these responses remains incompletely understood, with possibilities including receptor-level or cellular-level mechanisms.

Purpose of the Study:

• To investigate whether T-cell response thresholds are determined at the receptor or cellular level.
• To develop a mathematical model elucidating the impact of ligand properties and coreceptor interactions on T-cell signaling.
• To understand the mechanistic basis of T-cell response profiles.

Main Methods:

• Analysis of distinct functional responses in a clonal T-cell system.
• Utilizing a spectrum of biophysically defined altered peptide ligands across various concentrations.
• Derivation of a mathematical model for TCR/pMHC signaling kinetics.

Main Results:

• The cellular hypothesis, where cumulative signals are compared to thresholds, best explains the observed data.
• Ligand density, affinity, and off-rate distinctly influence T-cell signaling.
• TCR/pMHC class I dissociation rate was the primary kinetic factor under experimental conditions.
• The CD8 coreceptor modulated TCR/pMHCI interactions and altered peptide ligand potency.

Conclusions:

• T-cell response thresholds are established at the cellular level.
• A mathematical model quantifies the influence of TCR/pMHCI kinetics and CD8 on T-cell function.
• These findings provide a mechanistic framework for understanding T-cell response profiles.