Partially distinct molecular mechanisms mediate inhibitory FcgammaRIIB signaling in resting and activated B cells.
FcgammaRIIB functions as an inhibitory receptor to dampen B cell Ag receptor signals and immune responses. Accumulating evidence indicates that ex vivo B cells require the inositol 5-phosphatase, Src homology domain 2-containing inositol 5-phosphatase (SHIP), for FcgammaRIIB-mediated inhibitory signaling. However, we report here that LPS-activated primary B cells do not require SHIP and thus differ from resting B cells. SHIP-deficient B cell blasts display efficient FcgammaRIIB-dependent inhibition of calcium mobilization as well as Akt and extracellular signal-related protein kinase phosphorylation. Surprisingly, FcgammaRIIB-dependent degradation of phosphatidylinositol 3,4,5-trisphosphate and conversion into phosphatidylinositol 3,4-bisphosphate occur in SHIP-deficient B cell blasts, demonstrating the function of an additional inositol 5-phosphatase. Further analysis reveals that while resting cells express only SHIP, B cell blasts also express the recently described inositol 5-phosphatase, SHIP-2. Finally, data suggest that both SHIP-2 and SHIP can mediate downstream biologic consequences of FcgammaRIIB signaling, including inhibition of the proliferative response.
Brauweiler
A
A
Department of Immunology, National Jewish Medical and Research Center, Denver, CO 80206, USA.
Tamir
I
I
Marschner
S
S
Helgason
C D
CD
Cambier
J C
JC
D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D001402:B-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D002118:Calcium / Q000037:antagonists & inhibitors / Q000502:physiology; D020013:Calcium Signaling / Q000235:genetics / Q000276:immunology; D007399:Interphase / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011940:Receptor Aggregation / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000037:antagonists & inhibitors / Q000502:physiology; D017452:Receptors, IgG / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D018909:src Homology Domains / Q000235:genetics / Q000276:immunology
D015703:Antigens, CD; C080571:Fc gamma receptor IIB; D008070:Lipopolysaccharides; D018129:Phosphatidylinositol Phosphates; D011518:Proto-Oncogene Proteins; D011947:Receptors, Antigen, B-Cell; D017452:Receptors, IgG; C060974:phosphatidylinositol 3,4,5-triphosphate; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D010744:Phosphoric Monoester Hydrolases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D002118:Calcium