CD4+T-cells create a stable mechanical environment for force-sensitive TCR:pMHC interactions.

Area of Science:

• Immunology
• Biophysics
• Cell Biology

Background:

• Mechanical forces on T-cell receptors (TCR) are thought to influence T-cell antigen recognition and discrimination.
• However, the precise magnitude, frequency, and impact of these forces remain poorly understood.

Purpose of the Study:

• To quantitatively assess forces experienced by various T-cell receptor:pMHC pairs at single-molecule resolution.
• To investigate the role of these forces before and during T-cell activation, considering platforms with and without tangential force registration.

Main Methods:

• Utilized glass-supported lipid bilayers presenting pMHC, conjugated to a molecular force sensor.
• Incorporated adhesion and costimulatory molecules to engage approaching T-cells.
• Measured forces at single-molecule resolution across different TCR:pMHC pairs with varying bond lifetimes.

Main Results:

• CD4+ T-cell TCRs experience significantly lower forces than previously estimated.
• Only a small fraction of ligand-engaged TCRs encounter these forces during antigen scanning.
• These infrequent and minor mechanical forces do not affect the overall TCR:ligand bond lifetime.

Conclusions:

• The immunological synapse provides a stable biophysical environment.
• This stability prevents mechanical forces from disrupting antigen recognition by T-cells.