Activation of Human Peripheral IgM+ B Cells Is Transiently Inhibited by BCR-Independent Aggregation of FcγRIIB

Abstract

Immune complexes can trigger a SHIP-1-independent proapoptotic signal in mouse class-switched IgG+ B cells and plasma cells by binding to FcγRIIB, 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 FcγRIIB 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 FcγRIIB (IIA1.6-FcγRIIB), we also show that the unique aggregation of human FcγRIIB induces ITIM phosphorylation. This aggregation provokes the recruitment of phosphorylated SHIP-1 by FcγRIIB and inhibits the constitutive phosphorylation of Akt in human IIA1.6-FcγRIIB cells. This inhibitory signaling pathway is abrogated in IIA1.6 cells expressing ITIM-mutated FcγRIIB (FcγRIIBY292G), suggesting that ITIM phosphorylation is necessary for FcγRIIB-induced B cell blockade. Overall, we demonstrate that the unique aggregation of FcγRIIB on human peripheral IgM+ B cells is sufficient to transiently down-regulate their activation without inducing apoptosis. Our results suggest that FcγRIIB 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.