The role of peptidases and their endogenous inhibitors in the regulation of NK cell cytotoxicity

Abstract Cysteine cathepsins are implicated in various physiological and pathological processes. They play important roles in immune responses involving antigen processing and presentation, cytotoxicity of natural killer (NK) cells, cytotoxic T lymphocytes (CTLs), migration and adhesion of immune cells, cytokines, growth factor regulation, and toll-like receptor signaling. In NK cells, they activate granzymes and perforin from their precursor forms, molecules that are essential for the activation of the NK cell cytotoxicity. The process is regulated by cystatin F, an endogenous cysteine peptidase inhibitor, which colocalizes with cathepsins in endosomal/lysosomal vesicles and cytotoxic granules, and is capable of direct regulation of cathepsin activity. In the tumor microenvironment, several myeloid cells and cancer stem cells secrete cystatin F, which upon internalization may induce split anergy of NK cells decreasing their antitumor cytotoxicity and allowing secretion of cytokines, and/or completely impair the NK function.