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Btk Regulates B Cell Receptor-Mediated Antigen Processing and Presentation by Controlling Actin Cytoskeleton Dynamics in B Cells¹

Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742

The high efficiency of Ag processing and presentation by B cells requires Ag-induced BCR signaling and actin cytoskeleton reorganization, although the underlying mechanism for such requirements remains elusive. In this study, we identify Bruton’s tyrosine kinase (Btk) as a linker connecting BCR signaling to actin dynamics and the Ag transport pathway. Using xid mice and a Btk inhibitor, we show that BCR engagement increases actin polymerization and Wiskott-Aldrich syndrome protein activation in a Btk-dependent manner. Concurrently, we observe Btk-dependent increases in the levels of phosphatidylinositide-4,5-bisphosphate and phosphorylated Vav upon BCR engagement. The rate of BCR internalization, its movement to late endosomes, and efficiency of BCR-mediated Ag processing and presentation are significantly reduced in both xid and Btk inhibitor-treated B cells. Thus, Btk regulates actin dynamics and Ag transport by activating Wiskott-Aldrich syndrome protein via Vav and phosphatidylinositides. This represents a novel mechanism by which BCR-mediated signaling regulates BCR-mediated Ag processing and presentation.

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 is supported by a National Institutes of Health Grant AI059617 (to W.S.).

² Address correspondence and reprint requests to Dr. Wenxia Song, Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742. E-mail address: wenxsong{at}umd.edu

³ Abbreviations used in this paper: XL, cross-linking; AF, Alexa Fluor; B, basic; Btk, Bruton’s tyrosine kinase; CTX-B, cholera toxin subunit B; GBD, GTPase-binding domain; GEF, guanidine nucleotide exchange factor; HEL, hen egg lysozyme; PH, pleckstrin homology; PM, plasma membrane; PRD, proline-rich domain; PtdIns-4,5-P₂, phosphatidylinositol-4,5-bisphosphate; Tf, transferrin; VCA domains, verprolin homology, cofilin homology and acidic; WASP, Wiskott-Aldrich syndrome protein; oWASP, WASP with open and active conformation; pWASP, phosphorylated WASP; MFI, mean fluorescence intensity; wt, wild type; MZ, marginal zone.

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