Human neutrophils express low levels of FcgRIIIA, which plays a role in PMN activation

Abstract

We have identified a rare healthy FcgRIIIB (CD16B)-null donor completely lacking FCGR3B RNA and protein expression and dissected the role of the different neutrophil Fcg receptors in the response to therapeutic anti-CD20 monoclonal antibodies. We observed that polymorphonuclear neutrophils (PMNs) from FcgRIIIB wild-type (WT) individuals or the null donor were more effectively activated by chronic lymphocytic leukemia (CLL) B-cell targets opsonized with glycoengineered anti-CD20 antibodies compared with fully core-fucosylated anti-CD20 antibodies, suggesting the presence and role of FcgRIIIA (CD16A) on PMNs. Indeed, we demonstrated by reverse-transcription polymerase chain reaction, flow cytometry, and western blot analysis that PMNs from FcgRIIIB WT donors and the null individual express low levels of FcgRIIIA on their surfaces. FcgRIIIA is a functional and activating molecule on these cells, because anti-CD16 F(ab9)2 antibodies alone were able to activate highly purified PMNs from the FcgRIIIB-null donor. Use of blocking anti-CD16 and anti-CD32 antibodies showed that FcgRIIIA is also a major mediator of phagocytosis of CD20-opsonized beads by FcgRIIIB WT and null PMNs. In contrast, trogocytosis of antibody-opsonized CLL B cells by PMNs was mediated primarily by FcgRIIIB in WT PMNs and by FcgRIIA in null PMNs. We conclude that FcgRIIIA is an important player in PMN functions, whereas FcgRIIIB is dispensable for activation and phagocytosis. We discuss the clinical implications of these findings.