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 engagement 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 FcγR on human neutrophils. This GPI-anchored receptor lacks an intracellular domain. The mechanisms by which FcγRIIIb transduce signals remain unclear. A FcγRIIIb-deficient phenotype has been reported in apparently healthy adults, 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 adult brothers lacking FcγRIIIb on neutrophils and characterized their neutrophil activation through FcγR engagement by opsonized Escherichia coli. Sequencing of the FCGR3B gene revealed mutations in exon 2 resulting in translation loss. In the absence of stimulation, FcγRIIIbnull neutrophils showed unaltered levels of FcγRIIa, TLR-2, TLR-4 and TLR-6, but significantly higher FcγRIIIa and FcγRIa compared to FcγRIIIb-expressing controls. Upon challenge with opsonized E. coli, increased surface expression of FcγRIa, TLR-4, and αM integrin (CD11b) was observed exclusively in FcγRIIIbnull neutrophils. Antibacterial functions stimulated by opsonized E. coli were significantly lower in FcγRIIIbnull 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.