NKG2D signaling between human NK cells enhances TACE-mediated TNF-α release1

Natural killer group 2 member D (NKG2D) is a strong NK cell activating receptor, with engagement by ligands triggering granule release and cytokine production. The function of NKG2D signaling in NK cells has largely been studied in the context of engagement of the receptor by ligands expressed on the surface of target cells. We report that upon activation with IL-12, IL-15 and IL-18, human NK cells express NKG2D ligands of the UL16 binding protein (ULBP) family on the cell surface. NKG2D-ligand interaction between cytokine-stimulated NK cells increases the activity of the metalloprotease TNF-α-converting enzyme (TACE). This enhanced TACE activity significantly increases the release of TNF-α and ULBP proteins from the surface of the NK cells. These results demonstrate that NKG2D signaling is critical for maximal TNF-α release by NK cells. Further, they are the first to demonstrate a role for NKG2D-ligand interaction via homotypic NK cell contact in NK cell effector function.