GPI-anchor deficiency in myeloid cells causes impaired Fc R effector functions

Signaling by transmembrane immunoglobulin G (IgG)–Fc receptors (Fc Rs) in response to ligand involves association with membrane microdomains that contain glycosyl phosphatidylinositol (GPI)– anchored proteins. Recent in vitro studies showed enhancement of Fc R signaling by forced monoclonal antibody– mediated cocrosslinking with various GPIanchored proteins. Here, the possibility that GPI-anchored proteins are involved in normal physiologic Fc R effector functions in response to a model ligand was studied using myeloid-specific GPIanchor–deficient mice, generated by CreloxP conditional targeting. GPI-anchor– deficient primary myeloid cells exhibited normal Fc R expression and binding or endocytosis of IgG–immune complexes (IgG-ICs). Strikingly, after stimulation with IgG-ICs, tumor necrosis factorrelease, dendritic cell maturation, and antigen presentation were strongly reduced by GPIanchor deficiency. Tyrosine phosphorylation of the FcR -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 Fc R effector functions in vitro and in vivo. (Blood. 2004;104:2825-2831)