Lunatic and Manic Fringe Cooperatively Enhance Marginal Zone B Cell Precursor Competition for Delta-like 1 in Splenic Endothelial Niches

Hospital for Sick Children Research Institute, Toronto, ON, Canada.
Immunity (Impact Factor: 21.56). 03/2009; 30(2):254-63. DOI: 10.1016/j.immuni.2008.12.016
Source: PubMed


Notch2 activation induced by Delta-like-1 (DL1) drives development of splenic marginal zone (MZ) B cells, an innate-like lineage that protects against sepsis. DL1 interacts with Notch2 weakly, but it is not known whether enhancement of DL1-induced Notch2 activation by Fringe glycosyltransferases is important for MZ B cell development. Furthermore, DL1-expressing cells that promote MZ B cell development have not been identified. We show that Lunatic Fringe (Lfng) and Manic Fringe (Mfng) cooperatively enhanced the DL1-Notch2 interaction to promote MZ B cell development. We also identified radio-resistant red pulp endothelial cells in the splenic MZ that express high amounts of DL1 and promoted MZ B generation. Finally, MZ B cell precursor competition for DL1 homeostatically regulated entry into the MZ B cell pool. Our study has revealed that the Fringe-Notch2 interaction has important functions in vivo and provides insights into mechanisms regulating MZ B cell development.

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    • "Although Notch has long been known to regulate MZ B cell development, the stage at which Notch signaling exerts its effects is unknown. The ligand for Notch2, Dll1, is expressed on the luminal face of venules that are predominately found in the red pulp of the spleen, and some Dl1 expression is also present in the MZ [42]. Thus, Notch signaling would be activated when B cells migrate from blood vessels to the MZ or when B cells shuttle between the follicles and the MZ. "
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    ABSTRACT: Both the B cell antigen receptor (BCR) signaling and Notch signaling pathway play important roles in marginal zone (MZ) B cell development; however, if and how these two signaling pathways engage in crosstalk with each other remain unclear. In the present study, IgH transgenic mice (TgV(H)3B4) were crossed with mice with Notch downstream transcription factor RBP-J floxed alleles (RBP-J(f/f)) and Mx-Cre transgene. Subsequently, MZ B cell development was analyzed in 3B4/Cre/RBP-J(f/f) mice that expressed the transgenic 3B4 IgH and exhibited a deficiency in Notch signaling in B cells upon poly (I:C) injection. We observed that MZ B cell numbers were severely reduced, but still detectable in 3B4/Cre/RBP-J(f/f) mice, in contrast to increased numbers of MZ B cells in TgV(H)3B4 mice and almost no MZ B cells in Cre/RBP-J(f/f) mice. The majority of the MZ B cells in the 3B4/Cre/RBP-J(f/f) mice had the same antigen specificity with that of 3B4 antibody, indicating that a particular BCR specificity might direct MZ B cell development in the absence of Notch signaling. The number of MZ B precursor (MZP) cells was reduced sharply in 3B4/Cre/RBP-J(f/f) mice, and the number of transitional stage 1 and transitional stage 2 cells did not change that much, indicating that the interaction between BCR and Notch signaling likely occurred during the T2-MZP stage. Based on the transgenic mouse model, our data indicate that MZ B cells with certain BCR specificity can develop in a Notch-RBP-J independent manner.
    Full-text · Article · Jun 2012 · PLoS ONE
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    • "The preferential induction of Notch1 ICD by Jagged1-Fc stimulation and that of Notch2 ICD by Dll1-Fc stimulation supported this notion. Although we could not directly indicate the preferential Dll1/Notch2 and Jagged1/Notch1 interactions due to a lack of appropriate blocking mAbs against Notch1 and Notch2, such a preferential Notch2/Dll1 interaction also plays a key role in the development of marginal zone B cells in the spleen [25] and a preferential Notch1/Jagged1 interaction has been implicated in the maintenance of hematopoietic stem cells in the BM [26,27]. It has been known that interaction of Notch receptors with Dll versus Jagged ligands is affected by glycosylation of Notch extracellular domain by Fringe [28,29]. "
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