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 initiates 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 proteases can result in the rapid (within minutes) cell death of Ab-coated targets. However, little information is available as to whether NK cells can initiate subsequent killing through granule-independent mechanisms and as to the mechanisms that down-regulate NK cell-mediated responses. We demonstrate in this study that FcR stimulation of activated human 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 receptor. In addition, as resting NK cells become activated, their Fas receptors become competent to deliver autocrine suicide signals. We demonstrate in this work that the interaction of Fas ligand on the FcR-stimulated NK cells with their Fas receptors can result in apoptosis of the NK cells. These results suggest that the FcR-induced expression of Fas ligand on activated NK cells can critically influence the capacity of these cells to mediate paracrine and autocrine cell death.
Eischen
C M
CM
Department of Immunology, Mayo Clinic and Foundation, Rochester, MN 55905, USA.
Schilling
J D
JD
Lynch
D H
DH
Krammer
P H
PH
Leibson
P J
PJ
D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D001483:Base Sequence; D016923:Cell Death / Q000187:drug effects / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D053222:Fas Ligand Protein; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000096:biosynthesis; D011961:Receptors, Fc / Q000378:metabolism / Q000502:physiology*
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008024:Ligands; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011961:Receptors, Fc