DOWN-REGULATION OF FC-GAMMA RECEPTOR IIIA-ALPHA (CD16-II) ON NATURAL-KILLER-CELLS INDUCED BY ANTI-CD16 MAB IS INDEPENDENT OF PROTEIN-TYROSINE KINASES AND PROTEIN-KINASE-C

Downregulation of functionally relevant surface molecules has been sho wn to be a powerful regulatory mechanism of Ag surface expression that seems to be of general significance in vivo. CD16-II (Fc gamma RIIIA alpha) is the transmembrane form of the low-affinity receptor for IgG which is expressed on monocytes and NK cells. Occupancy of CD16-II rec eptor on NK cells induces expression of activation antigens, synthesis of cytokines, and lysis of antibody-coated target cells. Furthermore, after activation the receptor is downregulated from the cell surface. This downregulation could play a physiological role in the NK activat ion process via CD16 by releasing the antibody-coated target cell and halting signal transduction. The participation of PKC and PTKs in the activation of NK cells via CD16 is clearly established. Thus, we have considered of interest to study the mechanism of CD16-II downregulatio n in NK cells and the role played by these kinases in the process. The results show that 1,10-phenantroline, a specific inhibitor of Zn2+-de pendent metalloproteases, inhibits CD16 downregulation induced by CD16 crosslinking, thus suggesting that this process requires the activati on of a Zn2+ dependent metalloprotease as it occurs in PMA mediated CD 16 downregulation by shedding. Our results also demonstrate that CD16- II downregulation induced by CD16 crosslinking is independent of PKC a nd PTK activation. In contrast other NK cell activities induced by CD1 6 crosslinking, such as the induction of activation markers or the pro duction of TNF-alpha, were dependent of PTK activation. The fact that PKC inhibitor staurosporine blocks PMA- but not CD16-induced downregul ation suggests that CD16 downregulation can be achieved via two differ ent pathways: one that is PKC dependent and one that is not. The chara cterization of the Zn2+-dependent metalloproteases and the analysis of the regulatory mechanisms involved in its activation will be of inter est in order to clarify the physiological relevance of CD16-II release from NK cells as part of the NK activation process. (C) 1994 Academic Press, Inc.