FcγRIIB activation leads to inhibition of signalling by independently ligated receptors

The inhibitory IgG receptor, FcγRIIB, blocks signalling by co-aggregated antigen receptors on mature and activated B-cells. FcγRIIB is also expressed by immature B-cells; however, its function on these cells has not been defined. In the present paper, we demonstrate that immature B-cells are highly sensitive to inhibitory signalling mediated by FcγRIIB. Co-aggregation of FcγRIIB with the B-cell antigen receptor (BCR) on immature B-cells leads to near ablation of late phase calcium mobilization. Concomitant with enhanced inhibitory signalling, we found that Src-homology-2-domain-containing inositol 5′-phosphatase (SHIP) is expressed at much higher levels in immature B-cells than in mature B-cells. Perhaps most importantly, we report that SHIP activated by BCR–FcγRIIB co-aggregation inhibits independently ligated receptors whose signalling requires PtdIns(3,4,5)P₃. We found that stromal-derived factor 1 (SDF-1)-induced cell migration is impaired by prior activation of FcγRIIB. This inhibition is reduced in SHIP-deficient B-cells. Therefore receptor-mediated signalling responses that are dependent on PtdIns(3,4,5)P₃ are subject to both direct and indirect inhibition by FcγRIIB-activated SHIP.