Mechanical force determines chimeric antigen receptor microclustering and signaling

Area of Science:

• Immunology
• Cellular Biology
• Biophysics

Background:

• Chimeric antigen receptor (CAR) T-cell therapy is a successful clinical treatment.
• The precise mechanism initiating CAR signaling upon antigen binding is not fully understood.

Purpose of the Study:

• To investigate the role of mechanical force in CAR T-cell activation.
• To decouple microclustering and signaling events in CAR T-cells.

Main Methods:

• Utilized double-stranded DNA (dsDNA) tethers to apply controlled mechanical forces (12–51 pN) to antigens.
• Manipulated antigen tether forces to isolate microclustering and signaling.

Main Results:

• CAR microclustering and signaling are dependent on mechanical force during antigen binding.
• Cellular contractility generates the mechanical force for CAR microclustering.
• Strong adhesion and CAR diffusion confinement, driven by mechanical force, induce microclustering.
• Cytotoxicity may require a lower mechanical force threshold than cytokine generation.

Conclusions:

• CAR signaling is initiated by mechanical-force-induced microclustering.
• This study proposes a model where mechanical forces mediate CAR T-cell activation.