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

Area of Science:

• Immunology
• Biophysics
• Cancer Biology

Background:

• Immune checkpoint inhibitors targeting PD-1 are effective cancer therapies, but the precise mechanism of PD-1 signaling initiation by ligand binding is not fully understood.
• Soluble PD-L1, a prognostic marker in various cancers, binds PD-1 but does not suppress T cell function, suggesting a role for mechanical forces.
• Previous studies indicated T cells apply forces to PD-1-PD-L2 bonds, leading to the hypothesis that mechanical force is crucial for PD-1 triggering.

Approach:

• Investigated the role of mechanical force in PD-1 signaling by manipulating mechanical support on ligands.
• Utilized force spectroscopy to analyze PD-1 bond dynamics with PD-Ligands under varying forces.
• Employed steered molecular dynamics simulations to elucidate the structural and dynamic changes in the PD-1-PD-L2 complex under force.

Key Points:

• PD-1 function is diminished or abolished when mechanical support for ligand binding is reduced or removed.
• PD-1 forms catch bonds (<7 pN) that prolong lifetime and slip bonds (>8 pN) that accelerate dissociation with PD-Ligands.
• Force-induced interactions in the PD-1-PD-L2 complex, involving relative rotation and translation, are crucial for T cell suppression.
• Mutants disrupting force-induced interactions show reduced T cell suppression despite similar binding affinity.

Conclusions:

• Mechanical force is a critical regulator of PD-1 signaling, essential for effective T cell suppression in cancer immunity.
• The "catch bond" phenomenon, dependent on applied force, mediates PD-1's biological function.
• Cells can sense and utilize mechanical forces to regulate PD-1 pathway activation, offering novel therapeutic targets.