An ongoing production of IFN-α may be of etiopathogenic significance in systemic lupus erythematosus (SLE). It may be due to the natural IFN-producing cells (NIPC), also termed plasmacytoid dendritic cells (PDC), activated by immune complexes that contain nucleic acids derived from apoptotic cells. We here examined the role of FcγR in the IFN-α production in vitro by PBMC induced by the combination of apoptotic U937 cells and autoantibody-containing IgG from SLE patients (SLE-IgG). The Fc portion of the SLE-IgG was essential to induce IFN-α production, because Fab fragments or F (ab′) 2 were ineffective. Normal, especially heat-aggregated, IgG inhibited the IFN-α production, suggesting a role for FcγR on PBMC. Using blocking anti-FcγR Abs, the FcγRIIa, c (CD32) but not FcγRI or FcγRIII were shown to be involved in the IFN-α induction by apoptotic cells combined with SLE-IgG, but not by HSV or CpG DNA. In contrast, the action of all of these inducers was inhibited by the anti-FcγRIIa, b, c mAb AT10 or heat-aggregated IgG. Flow cytometric analysis revealed that∼ 50% of the BDCA-2-positive PBMC, ie, NIPC/PDC, expressed low but significant levels of FcγRII, as did most of the actual IFN-α producers activated by HSV. RT-PCR applied to NIPC/PDC purified by FACS demonstrated expression of FcγRIIa, but not of FcγRIIb or FcγRIIc. We conclude that FcγRIIa on NIPC/PDC is involved in the activation of IFN-α production by interferogenic immune complexes, but may also mediate inhibitory signals. The FcγRIIa could therefore have a key function in NIPC/PDC and be a potential therapeutic target in SLE.