Activation of human peripheral IgM(+) B cells is transiently inhibited by BCR-independent aggregation of Fc gamma RIIB

作者：Fournier Emilie M; Siberil Sophie; Costes Anne; Varin Audrey; Fridman Wolf Herman; Teillaud Jean Luc; Sautes Fridman Catherine^*

来源：The Journal of Immunology, 2008, 181(8): 5350-5359.

Immune complexes can trigger a SHIP-1-independent proapoptotic signal in mouse class-switched IgG(+) B cells and plasma cells by binding to Fc gamma RIIB, 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 gamma RIIB 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 gamma RIIB (IIA1.6-Fc gamma RIIB), we also show that the unique aggregation of human Fc gamma RIIB induces ITIM phosphorylation. This aggregation provokes the recruitment of phosphorylated SHIP-1 by Fc gamma RIIB and inhibits the constitutive phosphorylation of Akt in human IIA1.6-Fc gamma RIIB cells. This inhibitory signaling pathway is abrogated in IIA1.6 cells expressing ITIM-mutated Fc gamma RIIB (Fc gamma RIIBY292G), suggesting that ITIM phosphorylation is necessary for Fc gamma RIIB-induced B cell blockade. Overall, we demonstrate that the unique aggregation of Fc gamma RIIB on human peripheral IgM+ B cells is sufficient to transiently down-regulate their activation without inducing apoptosis. Our results suggest that Fc gamma RIIB 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.

• 出版日期2008-10-15