Selective blockade of the inhibitory Fcgamma receptor (FcgammaRIIB) in human dendritic cells and monocytes induces a type I interferon response program.
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.
Dhodapkar
Kavita M
KM
Lab of Cellular Physiology and Immunology, The Rockefeller University, New York, NY 10021, USA. dhodapk@rockefeller.edu
Banerjee
Devi
D
Connolly
John
J
Kukreja
Anjli
A
Matayeva
Elyana
E
Veri
Maria Concetta
MC
Ravetch
Jeffrey V
JV
Steinman
Ralph M
RM
Dhodapkar
Madhav V
MV
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*
D000906:Antibodies; D016207:Cytokines; C499173:FCGR2B protein, human; D007370:Interferon Type I; D017452:Receptors, IgG; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human