Notch1 engagement by Delta-like-1 promotes differentiation of B lymphocytes to antibody-secreting cells.
Notch signaling regulates B and T lymphocyte development and T cell effector class decision. In this work, we tested whether Notch activity affects mature B cell activation and differentiation to antibody-secreting cells (ASC). We show increased frequency of ASC in cultures of splenic B cells activated with LPS or anti-CD40 when provided exogenous Notch ligand Delta-like-1 (Dll1). Our results indicate that Notch-Dll1 interaction releases a default pathway that otherwise inhibits Ig secretion upon B cell activation. Thus, Dll1 enhanced spontaneous Ig secretion by naturally activated marginal zone B and B1 cells and reversed the inhibition of ASC differentiation mediated by B cell receptor crosslinking during LPS. Moreover, suppression of Notch signaling in B cell expression of either a dominant-negative mutant form of Mastermind-like 1 or a null mutation of Notch1 not only prevented Dll1-mediated enhancement of ASC differentiation but also reduced dramatically LPS-induced Ig secretion. Finally, we show that Dll1 and Jagged-1 are differentially expressed in discrete areas of the spleen, and that the effect of Notch engagement on Ig secretion is ligand-specific. These results indicate that Notch ligands participate in the definition of the mature B cell microenvironment that influences their terminal differentiation.
Santos
Margarida Almeida
MA
Instituto Gulbenkian de Ciência, 2781-901 Oeiras, Portugal.
Sarmento
Leonor Morais
LM
Rebelo
Manuel
M
Doce
Ana Agua
AA
Maillard
Ivan
I
Dumortier
Alexis
A
Neves
Helia
H
Radtke
Freddy
F
Pear
Warren S
WS
Parreira
Leonor
L
Demengeot
Jocelyne
J
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002454:Cell Differentiation; D004305:Dose-Response Relationship, Drug; D007136:Immunoglobulins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D000072100:Jagged-1 Protein; D008024:Ligands; D008070:Lipopolysaccharides / Q000737:chemistry / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D051881:Receptor, Notch1 / Q000235:genetics / Q000502:physiology*; D051880:Receptors, Notch / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D013154:Spleen / Q000378:metabolism
D002135:Calcium-Binding Proteins; C511877:Dll3 protein, mouse; D007136:Immunoglobulins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008024:Ligands; D008070:Lipopolysaccharides; D008565:Membrane Proteins; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins