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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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IMMUNOBIOLOGY

Notch activity synergizes with B-cell–receptor and CD40 signaling to enhance B-cell activation

Matthew Thomas1, Marco Calamito1, Bhaskar Srivastava1, Ivan Maillard2,3, Warren S. Pear1,2,4, and David Allman1

1 Department of Pathology and Laboratory Medicine, 2 Abramson Family Cancer Research Institute, 3 Department of Hematology/Oncology, and 4 Institute for Medicine & Engineering, University of Pennsylvania School of Medicine, Philadelphia

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 (BCR) and/or CD40 signaling to enhance several aspects of B-cell activation and function. We find that costimulation 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 coengagement 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 coengagement 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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 Proc. Natl. Acad. Sci. USAHome page
M. A. Santos, L. M. Sarmento, M. Rebelo, A. A. Doce, I. Maillard, A. Dumortier, H. Neves, F. Radtke, W. S. Pear, L. Parreira, et al.
Notch1 engagement by Delta-like-1 promotes differentiation of B lymphocytes to antibody-secreting cells
PNAS, September 25, 2007; 104(39): 15454 - 15459.
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