Mechanical force regulates ligand binding and function of PD-1.

Area of Science:

• Immunology
• Biophysics
• Molecular Biology

Background:

• Programmed cell death protein 1 (PD-1) blockade is a successful cancer therapy, but its signaling mechanism remains unclear.
• Soluble PD-L1 binds PD-1 but does not suppress T cell function, suggesting other factors are involved.

Purpose of the Study:

• To investigate the role of mechanical forces in PD-1 signaling.
• To elucidate how cells use forces to modulate PD-1-ligand interactions and downstream signaling.

Main Methods:

• Utilized biophysical techniques to measure PD-1-ligand bond dynamics under varying forces.
• Employed molecular dynamics simulations of the PD-1-PD-L2 complex.
• Assessed the function of PD-1 mutants with altered force-dependent interactions.

Main Results:

• PD-1 function is reduced when mechanical support on its ligand is removed.
• Cells apply forces to PD-1, creating catch bonds (<7 pN) and slip bonds (>8 pN), influencing bond lifetime.
• Force-induced molecular rotations and translations alter atomic contacts in the PD-1-PD-L2 complex.
• PD-1 mutants lacking catch bond properties showed reduced inhibitory function despite similar binding affinity.

Conclusions:

• Cellular forces are critical regulators of PD-1 signaling, distinct from simple binding affinity.
• Cells can dynamically modulate PD-1 signaling through mechanical force application.
• This force-gated mechanism offers new insights into immunotherapy and T cell regulation.