Quantitative analysis of the effect of CD16 ligation on human NK cell proliferation

CD16 (Fc gammaRIIIA), the low affinity receptor for IgG, is expressed on the majority of human peripheral blood NK cells. Ligation of CD16 with mAb or immune complexes activates NK cell cytotoxicity and cytokine secretion, and stimulates death of activated NK cells by apoptosis. This study uses NK cells labeled with the stable intracytoplasmic fluorescent dye 5- and 6-carboxyfluorescein diacetate succinimidyl ester to provide quantitative data on the effect of CD16 ligation on NK cell division and NK cell survival. When NK cells are cultured with rIL-2 and CD16 is ligated, NK cell division is stimulated, but there also is a substantial loss of NK progenitor cells. When NK cell proliferation is stimulated by coculture with gamma-irradiated MM-170 malignant melanoma cells and rIL-2, CD16 ligation enhances entry of NK cells into division. In some cases, CD16 ligation is essential for NK cell proliferation stimulated by MM-170 cells. In these cultures, there is no loss of NK progenitor cells. This study demonstrates that CD16 is an activation receptor for NK cell proliferation, and suggests that cellular costimulation alters the balance between NK cell death and NK cell proliferation stimulated by CD16 ligation.