Notch activity synergizes with B-cell-receptor and CD40 signaling to enhance B-cell activation.
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.
Thomas
Matthew
M
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 36th and Hamilton Walk, Philadelphia, PA 19104, USA.
Calamito
Marco
M
Srivastava
Bhaskar
B
Maillard
Ivan
I
Pear
Warren S
WS
Allman
David
D
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D007074:Immunoglobulin G / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000276:immunology*
D019013:CD40 Antigens; D007074:Immunoglobulin G; D011947:Receptors, Antigen, B-Cell; D051880:Receptors, Notch; D020928:Mitogen-Activated Protein Kinases