LFA-1 mechanical dose controls DNAM-1 signalling and perforin polarization in NK cells

Area of Science:

• Immunology
• Cell Biology
• Biophysics

Background:

• Natural killer (NK) cells are crucial for innate immunity against viruses and tumors.
• NK cell function is regulated by surface receptors, but the mechanical role of LFA-1 is unclear.
• Understanding LFA-1's mechanical contribution is vital for NK cell research.

Purpose of the Study:

• To investigate the mechanical properties of LFA-1 in NK cells.
• To elucidate how LFA-1 mediates mechanical forces influencing NK cell function.
• To precisely control and quantify LFA-1 tension and its downstream effects.

Main Methods:

• Utilized DNA-based tension gauge tethers (TGTs) functionalized with ICAM-1 to quantify and modulate LFA-1 tension.
• Employed multiplexed TGTs with combined unzip and shear geometries for controlled mechanical force delivery.
• Maintained constant molecular density to precisely modulate LFA-1-mediated adhesion force.

Main Results:

• Demonstrated fine-tuning of LFA-1-mediated mechanotransduction.
• Observed effects on LFA-1/DNAM-1 colocalization and perforin polarization.
• Found high-tension LFA-1/ICAM-1 interactions correlate with enhanced perforin polarization and receptor organization.

Conclusions:

• High-tension LFA-1/ICAM-1 interactions enhance NK cell activation.
• Mechanical forces mediated by LFA-1 are critical for immune synapse formation and function.
• This study provides a novel method for dissecting mechanotransduction in immune cells.