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Signaling in B Cell Antigen Receptor-Mediated Antigen Presentation1
,¶
* Department of Immunology, University of Manitoba, Winnipeg, Canada;
Tumor Immunology Unit, Department of Biological and Medical Research, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia;
Laboratory of Lymphocyte Signalling and Development, Molecular Immunology Programme, The Babraham Institute, Cambridge, United Kingdom;
Ludwig Institute for Cancer Research, London, United Kingdom;
¶ Department of Biochemistry and Molecular Biology, University College London, London, United Kingdom; and
|| ICOS, Bothell, WA 98021
The BCR serves to both signal cellular activation and enhance uptake and presentation of Ags by B cells; however, the intracellular signaling mechanisms linking the BCR to Ag presentation functions have been controversial. PI3Ks are critical signaling enzymes controlling many cellular processes, with the p110
isoform playing a critical role in BCR signaling. In this study, we used pharmacological and genetic approaches to evaluate the role of p110 signaling in Ag presentation by primary B lymphocytes. It was found that activation of allogeneic T cells is significantly reduced when B cells are pretreated with global PI3K inhibitors, but was intact when p110 signaling was specifically inactivated. In contrast, inactivation of p110 significantly impaired the ability of B cells to activate T cells in a BCR-mediated Ag uptake and presentation model. Prestimulation of p110-inactivated B cells with anti-CD40 or LPS could not rescue their BCR-mediated Ag presentation ability to normal levels. p110 signaling was required for efficient presentation of either anti-Ig or protein Ag via a lysozyme-specific BCR. p110-inactivated B cells were able to internalize Ag normally, and no defects in association of Ag with lysosome-associated membrane protein 1+ late endosomes were observed; however, these cells were less effective in forming polarized conjugates with Ag-specific T cells. Our data demonstrate a role for p110 signaling in B cell Ag presentation function, implicating 3-phosphoinositides and their targets in the latter stages of this process.
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 an operating grant from the Canadian Institutes of Health Research (to A.J.M.) and infrastructure support from the Canadian Foundation for Innovation. M.M.A.-A. was supported by a postdoctoral fellowship from the King Faisal Specialist Hospital and Research Centre and University of Manitoba Faculty Fund. A.J.M. was supported by a Canadian Institutes for Health Research New Investigator Award.
2 Address correspondence and reprint requests to Dr. Aaron J. Marshall, Department of Immunology, University of Manitoba, 730 William Avenue, Winnipeg, Manitoba, Canada R3E 0W3. E-mail address: marshall{at}ms.umanitoba.ca
3 Abbreviations used in this paper: MIIC, MHC class II-enriched compartment; HEL, hen egg lysozyme; LAMP, lysosome-associated membrane protein; MFI, mean fluorescence intensity; WM, wortmannin; WT, wild type; IC, IC87114.
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