Antibody-Dependent Neutrophil Phagocytosis of Plasmodium falciparum –Infected Erythrocytes Is Mediated by FcγRIIa

BACKGROUND: Fc gamma receptor III b (FcγRIIIb), a glycosylphosphatidylinositol-linked receptor, is the most abundant neutrophil FcγR on neutrophils, followed by FcγRIIa. FcγRs interact with IgG, and studies have reported the association of antibody-dependent neutrophil phagocytosis (ADNP) with protection against malaria; however, the role of specific FcγRs is not clear. METHODS: To investigate the relative importance of FcγRIIIb and FcγRIIa as mediators of the ADNP of Plasmodium falciparum-infected erythrocytes, purified neutrophils from healthy donors were treated with tumor necrosis factor (TNF) to mobilize the intracellular stores of FcγRIIIb to the surface, followed by enzymatic cleavage of glycosylphosphatidylinositol-linked FcγRIIIb with phosphatidylinositol phospholipase C (PIPLC). RESULTS: In TNF/PIPLC-treated neutrophils, detectable FcγRIII decreased by 79% (relative geometric mean fluorescence intensity, 21 ± 4.5 [mean ± SD]), while FcγRIIa detection increased by 82% (182 ± 2.3) as compared with untreated neutrophils (100%). When opsonized infected erythrocytes were incubated with TNF/PIPLC-treated neutrophils, ADNP by FcγRIIIb-depleted neutrophils increased significantly (relative phagocytosis, 585% ± 108%) as compared with untreated neutrophils (100%, P = .042). Using FcγR blocking, we show that when compared with no blocker (relative phagocytosis, 100%), ADNP was reduced >5-fold by FcγRIIa blocker alone (∼17% ± 1.5%, P < .05) and to a similar extent by combined FcγRIIa and FcγRIII blockers (∼24% ± 5.5%, P < .05). CONCLUSIONS: Our data suggest that FcγRIIa is the main phagocytic receptor that mediates the ADNP of infected erythrocytes and that FcγRIIIb acts as a decoy receptor.