Accumulation of dynamic catch bonds between TCR and agonist peptide-MHC triggers T cell signaling

Area of Science:

• Immunology
• Biophysics
• Cellular signaling

Background:

• T cell receptor (TCR)-pMHC interactions are crucial for initiating adaptive immune responses.
• The precise mechanisms by which mechanical force influences TCR-pMHC interactions and subsequent T cell signaling remain incompletely understood.

Purpose of the Study:

• To elucidate how mechanical force modulates TCR-pMHC bond dynamics.
• To investigate the relationship between force-dependent bond lifetimes and T cell activation signaling, specifically calcium (Ca2+) responses.

Main Methods:

• Utilized biophysical techniques to measure the lifetimes of single TCR-pMHC bonds under varying forces.
• Correlated bond lifetime dynamics with T cell calcium signaling responses.

Main Results:

• Mechanical force exhibits distinct effects on agonist and antagonist TCR-pMHC bonds: prolonging agonist bonds (catch bonds) and shortening antagonist bonds (slip bonds).
• Optimal T cell calcium responses were observed at specific force magnitudes (e.g., 10 pN), dependent on the force-lifetime relationship of both catch and slip bonds.
• Early and rapid accumulation of bond lifetimes, influenced by force, is critical for robust calcium signaling.

Conclusions:

• Force-dependent TCR-pMHC bond dynamics play a critical role in T cell activation.
• Agonist interactions form catch bonds that enable digital T cell triggering, while antagonist interactions form slip bonds that prevent activation.
• A model is proposed where the magnitude, duration, frequency, and timing of force on TCRs dictate downstream signaling events.