The final differentiation or maturation of dendritic cells (DCs) in response to environmental stimuli influences their ability to both initiate immunity and determine the quality of the response to antigens. Circulating immune complexes and cell-bound immunoglobulins present in normal human sera represent a potential stimulus for inadvertent DC activation in the steady state and during autoimmunity. Here, we show that selective blockade of the inhibitory Fc␥ receptor (Fc␥R) Fc␥RIIb with recently developed monoclonal antibodies leads to maturation of human monocytederived DCs, which depends on the presence of IgG in normal human plasma. Plasma, in the presence of an Fc␥RIIb blockade, caused the DCs to up-regulate the expression of costimulatory molecules and to produce the inflammatory mediator IL-12p70. Fc␥RIIb blockade of DCs loaded with tumor cells led to increased tumor-specific T cell immunity without the need for exogenous stimuli other than human plasma. Therefore, the activation status of DCs in the presence of normal human serum depends on the balance between activating and inhibitory Fc␥Rs and can be enhanced by new antibodies that react selectively with Fc␥RIIb. These data suggest an approach for modifying this balance to enhance immunity to immune complexes and antibody-coated tumor cells and to silence DC activation by immune complexes in autoimmune states.autoimmunity ͉ monoclonal antibody ͉ myeloma ͉ vaccination ͉ crosspresentation D endritic cells (DCs) are highly differentiated antigenpresenting cells that play a key role in the initiation and regulation of T cell immunity to pathogens and tumors while at the same time preventing immune responses against self-tissues or environmental antigens (1, 2). A critical property of DCs is that their ability to activate or inhibit immunity is linked to environmental stimuli, which determine their final differentiation or maturation status (3). Several stimuli, such as pathogens recognized by means of Toll-like receptors, CD40L, heat shock proteins, inflammatory cytokines, and innate lymphocytes, can lead to DC maturation and T cell immunity (2). However, under steady state, DCs must avoid inappropriate activation to prevent responses to self-antigens (''horror autotoxicus'') and harmless environmental antigens (4, 5). Specific pathways that prevent spontaneous DC activation are not as well understood as microbial and inflammatory stimuli.Circulating immune complexes and cell-bound immunoglobulins present in normal human sera represent a potential stimulus for DC activation in the steady state (6). The physiologic consequences of cell-bound IgG and immune complexes are modulated by a balance between activating and inhibitory Fc␥ receptors (Fc␥Rs) and include immune regulatory and inflammatory responses (7-10). Engagement of activating Fc␥Rs that contain an immune tyrosine-based activation motif on effector cells, including monocytes, neutrophils, natural killer cells, and mast cells, mediates phagocytosis, antibody-dependent cellmediated cytotoxicity, and r...
The ability of dendritic cells (DCs) to activate immunity is linked to their maturation status. In prior studies, we have shown that selective antibody-mediated blockade of inhibitory FcγRIIB receptor on human DCs in the presence of activating immunoglobulin (Ig) ligands leads to DC maturation and enhanced immunity to antibody-coated tumor cells. We show that Fcγ receptor (FcγR)–mediated activation of human monocytes and monocyte-derived DCs is associated with a distinct gene expression pattern, including several inflammation-associated chemokines, as well as type 1 interferon (IFN) response genes, including the activation of signal transducer and activator of transcription 1 (STAT1). FcγR-mediated STAT1 activation is rapid and requires activating FcγRs. However, this IFN response is observed without a detectable increase in the expression of type I IFNs themselves or the need to add exogenous IFNs. Induction of IFN response genes plays an important role in FcγR-mediated effects on DCs, as suppression of STAT1 by RNA interference inhibited FcγR-mediated DC maturation. These data suggest that the balance of activating/inhibitory FcγRs may regulate IFN signaling in myeloid cells. Manipulation of FcγR balance on DCs and monocytes may provide a novel approach to regulating IFN-mediated pathways in autoimmunity and human cancer.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.