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

Josée Golay, Rut Valgardsdottir, Gerta Musaraj, Damiano Giupponi, Orietta Spinelli and Martino Introna

Key points

  • Human neutrophils are shown here for the first time to express low levels of FcγRIIIA, usually masked by the high levels of homologous FcγRIIIB.

  • FcγRIIIA, but not FcγRIIIB, appears to mediate neutrophil activation by IgG antibodies as well as phagocytosis of antibody opsonized beads.

Abstract

We have identified a rare healthy FcγRIIIB (CD16B) Null donor completely lacking FCGR3B RNA and protein expression and have dissected the role of the different neutrophil Fc gamma receptors in the response to therapeutic anti-CD20 monoclonal antibodies. We observed that PMN from either FcγRIIIB wild type (WT) individuals or the Null donor were more effectively activated by CLL B-cell targets opsonized with glycoengineered compared to fully core-fucosylated anti-CD20 antibodies, suggesting the presence and role of FcγRIIIA (CD16A) on PMN. Indeed we demonstrated by RT-PCR, flow cytometry and Western blot analysis that PMN from both FcγRIIIB WT donors and the Null individual express low levels of FcγRIIIA on their surface. FcγRIIIA is a functional and activating molecule on these cells, since anti-CD16 F(ab')2 antibodies alone were able to activate highly purified PMN from the FcγRIIIB Null donor. Use of blocking anti-CD16 and -CD32 antibodies showed that FcγRIIIA is also a major mediator of phagocytosis of CD20 opsonized beads by both FcγRIIIB WT and Null PMN. In contrast, trogocytosis of antibody opsonized CLL B-cells by PMN was mediated mostly by FcγRIIIB in WT donors and FcγRIIA in Null PMN, respectively. We conclude that FcγRIIIA is an important player for PMN functions, whereas FcγRIIIB is dispensable for activation and phagocytosis. We discuss the clinical implications of these findings.

  • Submitted July 19, 2018.
  • Accepted January 9, 2019.