Fc gamma RIIB activation leads to inhibition of signalling by independently ligated receptors.
The inhibitory IgG receptor, Fc gamma RIIB, blocks signalling by co-aggregated antigen receptors on mature and activated B-cells. Fc gamma RIIB 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 Fc gamma RIIB. Co-aggregation of Fc gamma RIIB 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-Fc gamma RIIB co-aggregation inhibits independently ligated receptors whose signalling requires PtdIns(3,4,5) P (3). We found that stromal-derived factor 1 (SDF-1)-induced cell migration is impaired by prior activation of Fc gamma RIIB. This inhibition is reduced in SHIP-deficient B-cells. Therefore receptor-mediated signalling responses that are dependent on PtdIns(3,4,5) P (3) are subject to both direct and indirect inhibition by Fc gamma RIIB-activated SHIP.
Brauweiler
A M
AM
Integrated Department of Immunology, National Jewish Medical and Research Center and University of Colorado Health Sciences Center, 1400 Jackson Street, Denver, CO 80206, USA.
Cambier
J C
JC
D000818:Animals; D015703:Antigens, CD / Q000737:chemistry* / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002465:Cell Movement; D002633:Chemotaxis; D005434:Flow Cytometry; D015151:Immunoblotting; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry* / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D017452:Receptors, IgG / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors
D015703:Antigens, CD; C080571:Fc gamma receptor IIB; D011947:Receptors, Antigen, B-Cell; D017452:Receptors, IgG; D010744:Phosphoric Monoester Hydrolases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D002118:Calcium