Open AccessNotch1 engagement by Delta-like-1 promotes differentiation of B lymphocytes to antibody-secreting cells
Author(s) -
Margarida Albuquerque Almeida Santos,
Leonor M. Sarmento,
Manuel Rebelo,
Ana Agua-Doce,
Ivan Maillard,
Alexis Dumortier,
Hélia Neves,
Freddy Radtke,
Warren S. Pear,
Leonor Parreira,
Jocelyne Demengeot
Publication year - 2007
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0702891104
Subject(s) - notch signaling pathway , secretion , microbiology and biotechnology , b cell , biology , cd40 , effector , cellular differentiation , marginal zone , antibody , signal transduction , immunology , genetics , biochemistry , in vitro , gene , cytotoxic t cell
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.