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Inside-Out Regulation of FcRI (CD89) Depends on PP2A¹

Jantine E. Bakema^*, Annie Bakker^*, Simone de Haij^*, Henk Honing, Madelon Bracke, Leo Koenderman, Gestur Vidarsson, Jan G. J. van de Winkel^*,¶ and Jeanette H. W. Leusen^2,*

^* Immunotherapy Laboratory, Department of Immunology, University Medical Center Utrecht, Lundlaan, Department of Pulmonary Diseases, University Medical Center, and Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences, Utrecht, The Netherlands; Department Experimental Immunohematology, Sanquin Research, Plesmanlaan, Amsterdam, The Netherlands; and ^¶ Genmab, Yalelaan, Utrecht, The Netherlands

To achieve a correct cellular immune response toward pathogens, interaction between FcR and their ligands must be regulated. The Fc receptor for IgA, FcRI, is pivotal for the inflammatory responses against IgA-opsonized pathogens. Cytokine-induced inside-out signaling through the intracellular FcRI tail is important for FcRI-IgA binding. However, the underlying molecular mechanism governing this process is not well understood. In this study, we report that PP2A can act as a molecular switch in FcRI activation. PP2A binds to the intracellular tail of FcRI and, upon cytokine stimulation, PP2A becomes activated. Subsequently, FcRI is dephosphorylated on intracellular Serine 263, which we could link to receptor activation. PP2A inhibition, in contrast, decreased FcRI ligand binding capacity in transfected cells but also in eosinophils and monocytes. Interestingly, PP2A activity was found crucial for IgA-mediated binding and phagocytosis of Neisseria meningitidis. The present findings demonstrate PP2A involvement as a molecular mechanism for FcRI ligand binding regulation, a key step in initiating an immune response.

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 Dutch Cancer Foundation (KWF/NKB) Grant UU 2002 2706 and by the Association for International Cancer Research Grant 03-119.

² Address correspondence and reprint requests to Dr. Jeanette Leusen, Department of Immunology, Immunotherapy Laboratory, KC-02.085.2, University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, The Netherlands. E-mail address: j.h.w.leusen{at}umcutrecht.nl

³ Abbreviations used in this paper: Wt, wild type; m, murine; BD, binding domain; DC, dendritic cell; Cat, catharidin; Fos, fostriecin; Acs, ascomycin; p, phosphorylated.

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