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RIIB1
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* Institut National de la Santé et de la Recherche Médicale, Unité 872, Paris, France;
Centre de Recherche des Cordeliers, Université Pierre et Marie Curie-Paris 6, Unité Mixte de Recherche Scientifique 872, Paris, France; and
Université Paris Descartes, Unité Mixte de Recherche Scientifique 872, Paris, France
Immune complexes can trigger a SHIP-1-independent proapoptotic signal in mouse class-switched IgG+ B cells and plasma cells by binding to Fc
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 FcRIIB 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 FcRIIB (IIA1.6-FcRIIB), we also show that the unique aggregation of human FcRIIB induces ITIM phosphorylation. This aggregation provokes the recruitment of phosphorylated SHIP-1 by FcRIIB and inhibits the constitutive phosphorylation of Akt in human IIA1.6-FcRIIB cells. This inhibitory signaling pathway is abrogated in IIA1.6 cells expressing ITIM-mutated FcRIIB (FcRIIBY292G), suggesting that ITIM phosphorylation is necessary for FcRIIB-induced B cell blockade. Overall, we demonstrate that the unique aggregation of FcRIIB on human peripheral IgM+ B cells is sufficient to transiently down-regulate their activation without inducing apoptosis. Our results suggest that FcRIIB 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Institut National de la Santé et de la Recherche Médicale, Universités Paris Descartes-Paris 5, and Université Pierre et Marie Curie-Paris 6, and Canceropôle Île-de-France. E.M.F. was a recipient of a fellowship from the French Ministère de l’Enseignement Supérieur et de la Recherche and then from Association pour la Recherche sur le Cancer. S.S. was supported by Université Pierre et Marie Curie-Paris 6.
2 Current address: Institut National de la Santé et de la Recherche Médicale, Unité 768, Laboratoire du Développement Normal et Pathologique du Système Immunitaire, Université Paris Descartes, Paris F-75015, France.
3 J.-L.T. and C.S.-F. are senior coauthors.
4 Address correspondence and reprint requests to Dr. Catherine Sautès-Fridman, Team 13, Centre de Recherche des Cordeliers, Unité Mixte de Recherche Scientifique 872, 15 rue de l’Ecole de Médecine, 75006 Paris, France. E-mail address: catherine.fridman{at}crc.jussieu.fr
5 Abbreviations used in this paper: RAH, rabbit anti-human; PI, propidium iodide; GAM, goat anti-mouse; GAR, goat anti-rabbit.
6 The online version of this article contains supplemental material.
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