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

How diverse environmental cues are inte-grated to regulate B-cell activation and development remains poorly understood. Here we show that Notch activity syner-gizes with B-cell receptor (BCR) and/or CD40 signaling to enhance several as-pects 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 en-hances production of IgG1 cells in vitro and in vivo. We further find that coengage-ment of Notch and the BCR results in increased activation of the MAPK path-way, and MAPK and Notch inhibitors pre-vent 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 acti-vation. (Blood. 2007;109:3342-3350) © 2007 by The American Society of Hematolog