Activating and inhibitory IgG Fc receptors on human DCs mediate opposing functions
Adam M. Boruchov, … , Jeffrey V. Ravetch, James W. Young
Adam M. Boruchov, … , Jeffrey V. Ravetch, James W. Young
Published October 3, 2005
Citation Information: J Clin Invest. 2005;115(10):2914-2923. https://doi.org/10.1172/JCI24772.
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Research Article Immunology

Activating and inhibitory IgG Fc receptors on human DCs mediate opposing functions

Abstract

Human monocyte-derived DCs (moDCs) and circulating conventional DCs coexpress activating (CD32a) and inhibitory (CD32b) isoforms of IgG Fcγ receptor (FcγR) II (CD32). The balance between these divergent receptors establishes a threshold of DC activation and enables immune complexes to mediate opposing effects on DC maturation and function. IFN-γ most potently favors CD32a expression on immature DCs, whereas soluble antiinflammatory concentrations of monomeric IgG have the opposite effect. Ligation of CD32a leads to DC maturation, increased stimulation of allogeneic T cells, and enhanced secretion of inflammatory cytokines, with the exception of IL-12p70. Coligation of CD32b limits activation through CD32a and hence reduces the immunogenicity of moDCs even for a strong stimulus like alloantigen. Targeting CD32b alone does not mature or activate DCs but rather maintains an immature state. Coexpression of activating and inhibitory FcγRs by DCs reveals a homeostatic checkpoint for inducing tolerance or immunity by immune complexes. These findings have important implications for understanding the pathophysiology of immune complex diseases and for optimizing the efficacy of therapeutic mAbs. The data also suggest novel strategies for targeting antigens to the activating or inhibitory FcγRs on human DCs to generate either antigen-specific immunity or tolerance.

Authors

Adam M. Boruchov, Glenn Heller, Maria-Concetta Veri, Ezio Bonvini, Jeffrey V. Ravetch, James W. Young

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Monocytes, circulating conventional DCs, and cytokine-induced moDCs all ...
Monocytes, circulating conventional DCs, and cytokine-induced moDCs all express a range of FcγRs, whereas freshly isolated plasmacytoid DCs lack detectable surface expression of all FcγRs. Freshly isolated PBMCs were labeled with fluorochrome-conjugated mAbs. (A) After gating on HLA-DRbright PBMCs that were lineage marker negative, CD32a (left) and CD32b (right) were detected on CD123low conventional DCs (conv. DCs) but not on CD123bright plasmacytoid DCs (pDCs). (B) Monocytes were identified as CD14+ PBMCs. moDCs were studied as immature cells, gated according to characteristic phenotype (48) but lacking the surface CD83 expression of mature moDCs. Open histograms correspond to isotype controls, and filled histograms represent staining of the indicated FcγR. Most often, CD32a and CD32b were coexpressed on the same subpopulation of moDCs, as shown by a representative sample in C.