Identification of matrix metalloproteinases involved in the activation induced CD16 down-modulation by primary NK cells (172.9)

Abstract

CD16 (FcgammaRIIIa), the low affinity receptor for IgG is a potent activating receptor expressed by the majority of human natural killer (NK) cells that functions to mediate antibody-dependent cell-mediated cytotoxicity (ADCC). Since the bound IgG can be exchanged, the target cell recognition through CD16 gives NK cells flexibility in receptor specificity that can be manipulated for therapeutic purposes. ADCC dysfunction has been linked to cancer progression, poor prognosis and chronic infections; thus, understanding how CD16 expression is regulated by NK cells has clinical relevance. It is well established that upon activation NK cells enter into a refractory period in which CD16 expression is dramatically down-modulated, mainly due to the action of matrix metalloproteinases (MMPs). The aim of this project is to identify the MMP(s) responsible for CD16 cell surface down-modulation on activated NK cells and to determine if this down-modulation can be inhibited. Our data indicate that CD16 is down-modulated upon cell activation in primary NK cells, the released CD16 can be detected in the supernatant of the activated cells and a membrane-type MMP is involved in the process of CD16 shedding.