Natural killer cell-mediated shedding of ULBP2

UL16 binding proteins (ULBPs) are a family of cell surface proteins that are present in transformed and stressed cells and ligands for NKG2D. Soluble NKG2D ligands have been found in sera from cancer patients with their protein concentrations correlated with poor cancer prognosis. Here we show, for the first time, that human tumor cells lost their surface expression of ULBP2, but not ULBP1 and ULBP3, during NK cell-mediated cytolysis. In contrast to spontaneous shedding of NKG2D ligands, NK cytolysis-mediated shedding of ULBP2 was linked to target cell apoptosis, although both resulted from metalloproteinase cleavages. Inhibition of ULBP2 shedding by a metalloproteinase inhibitor BB-94 lead to reduced NK cell-mediated cytotoxicity and cytokine production. These results illustrate a regulation of NK cell effector functions through cytolysis-induced NKG2D ligand shedding. Consequently, compounds inhibiting NKG2D ligand shedding may offer therapeutic means to reduce excessive pathogenic NK cell activities.