FC RECEPTOR-INDUCED EXPRESSION OF FAS LIGAND ON ACTIVATED NK CELLS FACILITATES CELL-MEDIATED CYTOTOXICITY AND SUBSEQUENT AUTOCRINE NK CELL APOPTOSIS

Ligation of the Fc gamma R on NK cells by Ab-coated target cells initi ates a mode of killing referred to as antibody-dependent cell-mediated cytotoxicity (ADCC). There is clear evidence that the release from NK cells of granules containing pore-forming proteins and serine proteas es can result in the rapid (within minutes) cell death of Ab-coated ta rgets. However, little information is available as to whether NK cells can initiate subsequent killing through granule-independent mechanism s and as to the mechanisms that down-regulate NK cell-mediated respons es. We demonstrate in this study that FcR stimulation of activated hum an NK cells not only induces granule exocytosis, but also subsequently results in the transcriptional up-regulation of Fas ligand. These FcR -stimulated NK cells can then kill targets that bear Fas (CD95/APO-1), as this cytotoxicity can be inhibited by blocking Abs to the Fas rece ptor. In addition, as resting NK cells become activated, their Fas rec eptors become competent to deliver autocrine suicide signals. We demon strate in this work that the interaction of Fas ligand on the FcR-stim ulated NK cells with their Fas receptors can result in apoptosis of th e NK cells. These results suggest that the FcR-induced expression of F as ligand on activated NK cells can critically influence the capacity of these cells to mediate paracrine and autocrine cell death.