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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Various stimuli modulate the balanced expression of CD32a and CD32b on i...
Various stimuli modulate the balanced expression of CD32a and CD32b on immature moDCs. The indicated reagents were added to cultures of immature moDCs from day 3 to day 6. Expression of FcγRs was measured by flow cytometry (CD16 and CD64 not shown). Analyzed cells were immature or specifically gated for the absence of CD83 in cultures where there was a small amount of maturation (PGE2 and TNF-α). The mean fold changes (± SD) in the frequency of cells expressing a given FcγR induced by each reagent, compared with untreated cells, are shown in A. Density was calculated on the FcγR+ cells as the number of anti-FcγR antibodies bound per cell using a commercially available kit. The mean fold changes (±SD) in FcγR density induced by the reagents in 5 independent experiments, compared with the averaged FcγR densities on untreated/control moDCs, are shown in B. Sample histograms for untreated immature moDCs and IFN-γ–treated immature moDCs are shown in C. Open histograms correspond to isotype controls, and filled histograms show staining by the indicated anti-FcγR mAbs.