Cysteine protease-mediated cytoskeleton interactions with LFA-1 promote T-cell morphological changes.

Area of Science:

• Immunology
• Cell Biology
• Biochemistry

Background:

• T cells navigate complex biological barriers via amoeboid migration, involving cell polarization.
• The interaction between cathepsin X and lymphocyte function associated antigen 1 (LFA-1) influences T-cell morphology and uropod formation.

Purpose of the Study:

• To investigate the roles of cathepsin X and cathepsin L in T-cell migration and polarization.
• To elucidate the mechanism by which cathepsin X affects LFA-1 conformation and T-cell motility.

Main Methods:

• Inhibition of cathepsin X and cathepsin L activity in T cells.
• Assessment of actin polymerization, cell shape polarization, and chemotaxis.
• Analysis of cathepsin localization and LFA-1 modification within T cells.

Main Results:

• Inhibiting cathepsin X and cathepsin L significantly reduced T-cell actin polymerization, polarization, and chemotaxis.
• Cathepsin L activates procathepsin X in endolysosomal vesicles, with both proteases co-localizing at the uropod.
• Active cathepsin X cleaves the LFA-1 beta(2) cytoplasmic tail, inducing a high-affinity conformation that promotes talin binding and uropod elongation.

Conclusions:

• Cathepsin L and cathepsin X are crucial for T-cell migration by regulating actin dynamics and LFA-1 function.
• The proteolytic activity of cathepsin X on LFA-1 is essential for stabilizing the uropod and facilitating T-cell movement.
• These findings reveal a novel mechanism for protease-mediated immune cell trafficking.