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 (Fc{gamma}Rs) on neutrophil surfaces mediates multiple antimicrobial functions, including phagocytosis and the production of reactive oxygen species (ROS). Fc{gamma}RIIIb (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 Fc{gamma}RIIIb transduces signals remain unclear. A rare Fc{gamma}RIIIb-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 Fc{gamma}RIIIb on neutrophils and characterized their neutrophil activation through Fc{gamma}R crosslinking by immune complexes. Sequencing of the FCGR3B gene revealed mutations in exon 2 resulting in translation loss. In the absence of stimulation, Fc{gamma}RIIIbnull neutrophils showed unaltered levels of Fc{gamma}RIIa, TLR-2, TLR-4 and TLR-6, but significantly higher Fc{gamma}RIIIa and Fc{gamma}RIa. Upon challenge with E. coli immune complexes, increased surface expression of Fc{gamma}RIa, TLR-4, and M integrin (CD11b) was observed exclusively in Fc{gamma}RIIIbnull neutrophils. Antibacterial functions stimulated by immune complexes were significantly lower in Fc{gamma}RIIIbnull neutrophils, including phagocytic capacity and ROS production compared to Fc{gamma}RIIIb-expressing neutrophils. Overall, the absence of Fc{gamma}RIIIb on human neutrophils correlated with impaired antimicrobial functions following stimulation through Fc{gamma}Rs. This study provides new insights into the functional relevance of Fc{gamma}RIIIb and emphasizes the importance of this receptor in neutrophil responses to bacteria.