Ligand binding to Fc gamma R induces c-myc-dependent apoptosis in IL-2-stimulated NK cells.
The role of signals transduced via Fc gamma RIIIA in the modulation of the proliferative potential of NK cells has been investigated. Fc gamma R stimulation does not induce NK cell proliferation, and inhibits that induced by IL-2, but not by IL-12, as measured by [3H]TdR incorporation, without affecting entrance or progression through cell cycle. The inhibitory effect depends, at least in part, on induced apoptosis of the cells, detected by both light and electron microscopy examination. Fc gamma R stimulation induces apoptosis only in NK cells that have been previously activated by IL-2: this occurs within 3 h from receptor stimulation and is independent from de novo receptor-induced RNA or protein synthesis, but requires receptor-induced activation of protein tyrosine kinases and extracellular Ca2+ influx. IL-2 induces accumulation of c-myc mRNA in NK cells, and treatment of the cells with c-myc antisense oligodeoxyribonucleotides during the IL-2 stimulation phase inhibits the susceptibility to Fc gamma RIIIA-induced cell death, indicating that the induction of sustained levels of this proto-oncogene is necessary for the phenomenon. Thus, a two-step model is suggested for the Fc gamma R-induced apoptosis in IL-2 activated NK cells: the first step involves induced expression of c-myc, and possibly other permissive factors, upon IL-2 prestimulation; the second depends directly on the stimulation of the receptor, independently of additional gene induction. The evidence presented here suggests a mechanism of control of NK cell expansion at the latest stages of Ab-dependent immune responses.
Azzoni
L
L
Department of Microbiology and Immunology, Thomas Jefferson University, Jefferson Cancer Institute, Philadelphia, PA 19107.
Anegon
I
I
Calabretta
B
B
Perussia
B
B
D017209:Apoptosis / Q000276:immunology*; D001483:Base Sequence; D015152:Blotting, Northern; D002118:Calcium / Q000378:metabolism; D002453:Cell Cycle / Q000276:immunology; D002460:Cell Line; D015870:Gene Expression / Q000276:immunology; D016259:Genes, myc / Q000235:genetics*; D006801:Humans; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D000090063:Proto-Oncogene Mas; D017452:Receptors, IgG / Q000276:immunology* / Q000378:metabolism
D007376:Interleukin-2; C000715470:MAS1 protein, human; D016376:Oligonucleotides, Antisense; D000090063:Proto-Oncogene Mas; D017452:Receptors, IgG; D011505:Protein-Tyrosine Kinases; D002118:Calcium