Human IgG3 displays the strongest effector functions of all IgG subclasses but has a short half-life for unresolved reasons. Here we show that IgG3 binds to IgG-salvage receptor (FcRn), but that FcRn-mediated transport and rescue of IgG3 is inhibited in the presence of IgG1 due to intracellular competition between IgG1 and IgG3. We reveal that this occurs because of a single amino acid difference at position 435, where IgG3 has an arginine instead of the histidine found in all other IgG subclasses. While the presence of R435 in IgG increases binding to FcRn at neutral pH, it decreases binding at acidic pH, affecting the rescue efficiency—but only in the presence of H435–IgG. Importantly, we show that in humans the half-life of the H435-containing IgG3 allotype is comparable to IgG1. H435–IgG3 also gave enhanced protection against a pneumococcal challenge in mice, demonstrating H435–IgG3 to be a candidate for monoclonal antibody therapies.

Here, we report that the MHC class I-related neonatal Fc receptor (FcRn) is expressed within azurophilic and specific granules of neutrophils and relocates to phagolysosomes on phagocytosis of IgGopsonized bacteria. We found FcRn to enhance phagocytosis in a pH-dependent manner which was independent of IgG recycling. IgG-opsonized bacteria were inefficiently phagocytosed by neutrophils from ␤2M knock-out or FcRn ␣-chain knock-out mice, which both lack expression of FcRn. Similarly, low phagocytic activity was also observed with mutated IgG (H435A), which is incapable of binding to FcRn, while retaining normal binding to classical leukocyte IntroductionPhagocytic cells express members of 3 classes of leukocyte IgG-Fc receptors, Fc␥RI, Fc␥RII, and Fc␥RIII. All share considerable structural and functional homology and recognize similar residues within the CH2 region of IgG. 1 Fc␥R activates phagocytes on interaction with IgGopsonized particles, involving immunoreceptor tyrosine-based activation motifs (ITAMs). This activation signal may possibly be downregulated by the immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing Fc␥RIIb receptor on polymorphonuclear neutrophils (PMNs) and monocytes. 2 No other signaling motifs have been implicated in Fc␥R-mediated phagocytosis. Crosslinking of ITAM-bearing receptors (eg, T-cell receptor, Fc⑀RI) does not initiate phagocytosis, but it generally triggers fusion and release of granule contents into sealed immunologic synapses between effector cells and targets. In phagocytes these granules contain various components, including enzyme complexes that initiate the respiratory burst and phagosome acidification, as well as antimicrobial peptides and enzymes that serve to kill invading pathogens. 3,4 A distinct IgG receptor, the neonatal Fc␥R (FcRn), consisting of a unique ␣-chain and ␤2-microglobulin (␤2M), is a major histocompatibility class I (MHC-I) homolog. 5 FcRn is present in epithelial cells, placental syncytiotrophoblasts, as well as endothelial cells. In these cells, FcRn has been implicated in transport of IgG across mucosal cells, 5,6 from mother to fetus, 7 and regulation of IgG half-life, [8][9][10][11] respectively. This receptor has been found in human monocytes, 12 albeit that no function has been attributed to monocyte FcRn. FcRn does not bind IgG at physiologic pH (7.4). Only in the acidic environment of endocytic vacuoles (pH Յ 6.5), where histidine residues in the Fc-tail of IgG become protonated, can FcRn bind IgG with high affinity. Both ␤2M and the FcRn ␣-chain participate in IgG binding within the CH2-CH3 interface. 13 In this study we document expression of FcRn within PMNs. Furthermore, we observed FcRn translocation to nascent phagosomes, where FcRn facilitates IgG-mediated bacterial phagocytosis through signaling motifs found within the cytoplasmic tail. These results point to a novel role for FcRn in phagocyte biology. Materials and methods Recombinant antipneumococcal 6A/B antibodiesThe generation and functional characterization in vitro a...