Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 115, Issue 10, Pages 2914-2923Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI24772
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Funding
- NCI NIH HHS [R01 CA083070, P01CA23766, P01 CA023766, P01 CA59350, P01 CA059350, R01 CA83070] Funding Source: Medline
- NIAID NIH HHS [P01 AI 51573, P01 AI051573] Funding Source: Medline
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Human monocyte-derived DCs (moDCs) and circulating conventional DCs coexpress activating (CD32a) and inhibitory (CD32b) isoforms of IgG Fc gamma receptor (Fc gamma R)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-gamma most potently favors CD32a expression on immature DCs, whereas soluble antinflammatory 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 Fc gamma Rs 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 Fc gamma Rs on human DCs to generate either antigen-specific immunity or tolerance.
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