Activating and inhibitory IgG Fc receptors on human DCs mediate opposing functions
Adam M. Boruchov, Glenn Heller, Maria-Concetta Veri, Ezio Bonvini, Jeffrey V. Ravetch, James W. Young
Adam M. Boruchov, Glenn Heller, Maria-Concetta Veri, Ezio Bonvini, Jeffrey V. Ravetch, James W. Young
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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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Targeting CD32a or CD32b affects DC allostimulatory capacity in the MLR....
Targeting CD32a or CD32b affects DC allostimulatory capacity in the MLR. Two days after ligating CD32a, CD32b, both, or neither on immature moDCs, the moDCs were harvested and washed. These moDCs were then recultured at varying doses with 105 allogeneic T cells in triplicate round-bottomed 96-microwell plates without additional cytokines. DC doses ranged from 3,000 to 300 cells per well, yielding DC:T cell ratios from 1:30 to 1:300. [3H]TdR uptake by proliferating allogeneic T cells over the last 12 hours of a 4–5 day culture was measured as an index of DC immunogenicity. (A) The averaged triplicate values (mean ± SEM) for [3H]TdR incorporation by T cells stimulated in 4 independent experiments using samples derived from CD32a131HH or -HR donors are depicted logarithmically (log2) on the y-axis. (B) Experiments using samples from CD32a131RR donors were performed in parallel, with immobilized mouse or human IgG ligating FcγRs on the immature moDCs. The averaged triplicate values (mean ± SEM) from 3 independent experiments are depicted logarithmically (log2) on the y axis. Differences between conditions in A and B were tested using a stratified (by DC:T cell ratios) permutation t test.