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Blood, 15 April 2007, Vol. 109, No. 8, pp. 3342-3350.
Prepublished online as a Blood First Edition Paper on December 19, 2006; DOI 10.1182/blood-2006-09-046698.
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Submitted September 11, 2006
Accepted December 2, 2006
Notch activity synergizes with B cell receptor and CD40 signaling to enhance B cell activation
Matthew Thomas, Marco Calamito, Bhaskar Srivastava, Ivan Maillard, Warren S Pear, and David Allman*
Dept of Pathology & Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA
Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA
Institute for Medicine & Engineering, University of Pennsylvania School of Medicine, Philadelphia, PA
* Corresponding author; email: dallman{at}mail.med.upenn.edu.
How diverse environmental cues are integrated to regulate B cell activation and development remains poorly understood. Here we show that Notch activity synergizes with B cell receptor and/or CD40 signaling to enhance several aspects of B cell activation and function. We find that co-stimulation of follicular B cells with the Notch ligand Delta-like-1 leads to significant increases in BCR- and CD40-mediated proliferation, and enhances production of IgG1+ cells in vitro and in vivo. We further find that co-engagement of Notch and the BCR results in increased activation of the MAPK pathway, and MAPK and Notch inhibitors prevent B cell activation events mediated by co-engagement of Notch and the BCR. These data suggest that the BCR and CD40 signaling pathways collaborate with the Notch pathway to optimize B cell activation.

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