FcγRIIIb-deficient neutrophils have defects in ROS production, phagocytosis and actin polymerization following stimulation through FcγRs

Neutrophils are crucial to innate immune responses to microbes. The crosslinking of opsonized pathogens by Fc gamma receptors (FcγRs) on neutrophil surfaces mediates multiple antimicrobial functions, including phagocytosis and the production of reactive oxygen species (ROS). FcγRIIIb (CD16b) is the most abundant receptor on human neutrophils. It is a GPI-anchored receptor that lacks an intracellular domain. The exact mechanisms by which FcγRIIIb transduces signals remain unclear. A rare FcγRIIIb-deficient phenotype has been reported in apparently healthy subjects, which is intriguing given the abundance of this receptor on neutrophil surfaces and its crucial role in neutrophil activation by immune complexes. Here, we identified 2 healthy brothers lacking FcγRIIIb on neutrophils and characterized their neutrophil activation through FcγR crosslinking by immune complexes. Sequencing of the FCGR3B gene revealed mutations in exon 2 resulting in translation loss. In the absence of stimulation, FcγRIIIb ^null neutrophils showed unaltered levels of FcγRIIa, TLR-2, TLR-4 and TLR-6, but significantly higher FcγRIIIa and FcγRIa. Upon challenge with E. coli immune complexes, increased surface expression of FcγRIa, TLR-4, and αM integrin (CD11b) was observed exclusively in FcγRIIIb ^null neutrophils. Antibacterial functions stimulated by immune complexes were significantly lower in FcγRIIIb ^null neutrophils, including phagocytic capacity and ROS production compared to FcγRIIIb-expressing neutrophils. Overall, the absence of FcγRIIIb on human neutrophils correlated with impaired antimicrobial functions following stimulation through FcγRs. This study provides new insights into the functional relevance of FcγRIIIb and emphasizes the importance of this receptor in neutrophil responses to bacteria.