title: Activation of human peripheral IgM+ B cells is transiently inhibited by BCR-independent aggregation of Fc gammaRIIB.
abstract: Immune complexes can trigger a SHIP-1-independent proapoptotic signal in mouse class-switched IgG(+) B cells and plasma cells by binding to Fc gammaRIIB, in the absence of concomitant coaggregation with BCR, hence regulating plasma cell survival and participating in the selection of B cells producing high affinity Abs during secondary Ab responses. By contrast, we demonstrate in the present study that the unique aggregation of Fc gammaRIIB on human peripheral IgM(+) B cells does not induce apoptosis but transiently inhibits B cell proliferation and calcium influx triggered by BCR cross-linking. Using human peripheral B cells and IIA1.6 lymphoma B cells expressing wild-type human Fc gammaRIIB (IIA1.6-Fc gammaRIIB), we also show that the unique aggregation of human Fc gammaRIIB induces ITIM phosphorylation. This aggregation provokes the recruitment of phosphorylated SHIP-1 by Fc gammaRIIB and inhibits the constitutive phosphorylation of Akt in human IIA1.6-Fc gammaRIIB cells. This inhibitory signaling pathway is abrogated in IIA1.6 cells expressing ITIM-mutated Fc gammaRIIB (Fc gammaRIIB(Y292G)), suggesting that ITIM phosphorylation is necessary for Fc gammaRIIB-induced B cell blockade. Overall, we demonstrate that the unique aggregation of Fc gammaRIIB on human peripheral IgM(+) B cells is sufficient to transiently down-regulate their activation without inducing apoptosis. Our results suggest that Fc gammaRIIB could negatively regulate IgM(+) B cells before class-switch occurrence and that its unique engagement by immune complexes represents a reversible checkpoint for peripheral IgM(+) B cells.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 872, Paris, France.
authors.forename: Emilie M
authors.initials: EM
authors.lastname: Fournier
authors.forename: Sophie
authors.initials: S
authors.lastname: Sibéril
authors.forename: Anne
authors.initials: A
authors.lastname: Costes
authors.forename: Audrey
authors.initials: A
authors.lastname: Varin
authors.forename: Wolf-Herman
authors.initials: WH
authors.lastname: Fridman
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Teillaud
authors.forename: Catherine
authors.initials: C
authors.lastname: Sautès-Fridman
mesh_terms: D019943:Amino Acid Substitution / Q000276:immunology; D000818:Animals; D000936:Antigen-Antibody Complex / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D020013:Calcium Signaling / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D006801:Humans; D007075:Immunoglobulin M; D000072181:Inositol Polyphosphate 5-Phosphatases; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D020125:Mutation, Missense / Q000276:immunology; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D010950:Plasma Cells / Q000276:immunology* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051562:Proto-Oncogene Proteins c-bcr / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology*
chemical_list: D000936:Antigen-Antibody Complex; C080571:Fc gamma receptor IIB; D007075:Immunoglobulin M; D017452:Receptors, IgG; C496613:BCR protein, human; D051057:Proto-Oncogene Proteins c-akt; D051562:Proto-Oncogene Proteins c-bcr; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606430:INPP5D protein, human; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases