GPI-anchor deficiency in myeloid cells causes impaired FcgammaR effector functions.
Signaling by transmembrane immunoglobulin G (IgG)-Fc receptors (FcgammaRs) in response to ligand involves association with membrane microdomains that contain glycosyl phosphatidylinositol (GPI)-anchored proteins. Recent in vitro studies showed enhancement of FcgammaR signaling by forced monoclonal antibody-mediated cocrosslinking with various GPI-anchored proteins. Here, the possibility that GPI-anchored proteins are involved in normal physiologic FcgammaR effector functions in response to a model ligand was studied using myeloid-specific GPI-anchor-deficient mice, generated by Cre-loxP conditional targeting. GPI-anchor-deficient primary myeloid cells exhibited normal FcgammaR expression and binding or endocytosis of IgG-immune complexes (IgG-ICs). Strikingly, after stimulation with IgG-ICs, tumor necrosis factor-alpha release, dendritic cell maturation, and antigen presentation were strongly reduced by GPI-anchor deficiency. Tyrosine phosphorylation of the FcR gamma-chain in response to IgG-IC was impaired in GPI-anchor-deficient cells. Myeloid GPI-anchor deficiency resulted in attenuated in vivo inflammatory processes during IgG-IC-mediated alveolitis. This study provides the first genetic evidence for an essential role of GPI-anchored proteins in physiologic FcgammaR effector functions in vitro and in vivo.
Hazenbos
Wouter L W
WL
Department of Immunoregulation, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
Clausen
Björn E
BE
Takeda
Junji
J
Kinoshita
Taroh
T
D000818:Animals; D017951:Antigen Presentation; D000936:Antigen-Antibody Complex; D003713:Dendritic Cells / Q000166:cytology; D017261:Glycosylphosphatidylinositols / Q000172:deficiency* / Q000502:physiology; D007074:Immunoglobulin G; D007249:Inflammation; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000737:chemistry* / Q000502:physiology; D010766:Phosphorylation; D017452:Receptors, IgG / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014443:Tyrosine
D000936:Antigen-Antibody Complex; D017261:Glycosylphosphatidylinositols; D007074:Immunoglobulin G; D008024:Ligands; D017452:Receptors, IgG; D014409:Tumor Necrosis Factor-alpha; D014443:Tyrosine