title: Selective blockade of the inhibitory Fcgamma receptor (FcgammaRIIB) in human dendritic cells and monocytes induces a type I interferon response program.
abstract: 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 FcgammaRIIB 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 Fcgamma receptor (FcgammaR)-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). FcgammaR-mediated STAT1 activation is rapid and requires activating FcgammaRs. 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 FcgammaR-mediated effects on DCs, as suppression of STAT1 by RNA interference inhibited FcgammaR-mediated DC maturation. These data suggest that the balance of activating/inhibitory FcgammaRs may regulate IFN signaling in myeloid cells. Manipulation of FcgammaR balance on DCs and monocytes may provide a novel approach to regulating IFN-mediated pathways in autoimmunity and human cancer.
authors.affiliation: Lab of Cellular Physiology and Immunology, The Rockefeller University, New York, NY 10021, USA. dhodapk@rockefeller.edu
authors.forename: Kavita M
authors.initials: KM
authors.lastname: Dhodapkar
authors.forename: Devi
authors.initials: D
authors.lastname: Banerjee
authors.forename: John
authors.initials: J
authors.lastname: Connolly
authors.forename: Anjli
authors.initials: A
authors.lastname: Kukreja
authors.forename: Elyana
authors.initials: E
authors.lastname: Matayeva
authors.forename: Maria Concetta
authors.initials: MC
authors.lastname: Veri
authors.forename: Jeffrey V
authors.initials: JV
authors.lastname: Ravetch
authors.forename: Ralph M
authors.initials: RM
authors.lastname: Steinman
authors.forename: Madhav V
authors.initials: MV
authors.lastname: Dhodapkar
mesh_terms: D000906:Antibodies / Q000494:pharmacology; D015153:Blotting, Western; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D007370:Interferon Type I / Q000276:immunology* / Q000378:metabolism; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference; D017452:Receptors, IgG / Q000037:antagonists & inhibitors*; D050794:STAT1 Transcription Factor / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D000906:Antibodies; D016207:Cytokines; C499173:FCGR2B protein, human; D007370:Interferon Type I; D017452:Receptors, IgG; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human