The functional properties of Fcγ RI, II and III on myeloid cells: A comparative study of killing of erythrocytes and tumor cells mediated through the different Fc receptors

Abstract

Three distinct Fc receptors for IgG, Fcγ RI, Fcγ RII and Fcγ RIII are known to be associated with human myeloid cells. Using mAb specific for these receptors, and the hydridoma cells lines that produce these mAb, we have examined the ability of each of these receptors on different myeloid cells and cell lines to mediate killing of tumor and red cell targets. Hybridoma cells (HC) expressing anti-Fcγ RI, Fcγ RII or Fcγ RIII upon their surface were used as model self-directed tumor targets. Chicken erythrocytes (CE) were used as another type of target cell and in this case effector cell cytotoxicity was mediated by heteroantibodies (HA) composed of Fab fragments of anti-Fcγ R mAb covalently linked to Fab fragments of rabbit anti-CE antibodies. Monocytes, lymphocytes, polymorphonuclear cells (PMNs) and the myeloid cell lines U937, HL-60 and THP-l were used as effector cells either in their native state or after activation with rIFN-γ. Direct comparison of cytotoxicity by the same effector cell population against both tumor and erythroid targets has permitted definitive evaluation of the ability of the different Fcγ R to promote cytolysis under two different conditions. Monocytes were able to utilize Fcγ RI, Fcγ RII and Fcγ RIII in killing both CE and HC targets, and incubation with rIFN-γ augmented their ability to kill CE, particularly through Fcγ RI. Fcγ RII and Fcγ RIII mediated killing of CE by untreated neutrophils. rIFN-γ induced PMNs to express Fcγ RI and to mediate killing of CE through this receptor. Moreover, HC targets were not lyzed by untreated neutrophils, but rIFN-γ activated neutrophils killed HC bearing surface anti-Fcγ RI and anti-Fcγ RII, but not anti-Fcγ RIII. Myeloid cell lines HL-60 and U937 were unable to perform cytotoxicity without prior culture with rIFN-γ, following which they killed CE through Fcγ RI and Fcγ RII, but were still incapable of HC lysis. THP-l, another myeloid cell line, was cytotoxic to CE through Fcγ RI and Fcγ RII without activation. Following rIFN-γ treatment, cytotoxicity through these two Fcγ R increased and was also mediated by Fcγ RIII but these cells were still unable to kill HC. However, after culture under conditions which promoted a macrophage-like phenotype, THP-l cells acquired the ability to kill HC through Fcγ RI and Fcγ RII. When differentiated THP-l cells were also stimulated with rIFN-γ, killing of HC was augmented and was mediated by Fcγ RI, Fcγ RII and Fcγ RIII. Thus, untreated monocytes performed cytotoxicity of CE and HC through all three Fcγ R, whereas untreated neutrophils performed killing of CE only through Fcγ RII and Fcγ RIII and killed HC only after treatment with IFN-γ and only through Fcγ RI and Fcγ RII. Fcγ RIII on PMNs was unable to promote tumor cell killing even after IFN-γ activation of these cells. These studies indicate that the different Fcγ R on the various effector cell populations have distinct abilities to mediate cytotoxicity of tumor and red cell targets.