title: Differential regulation of Notch ligands in dendritic cells upon interaction with T helper cells.
abstract: The Notch signalling pathway has recently been linked to T helper 1 (Th1)/T helper 2 (Th2) cell polarization via a mechanism involving differential expression of Notch ligands, Delta-like and Jagged, in antigen-presenting cells. However, whether stimuli other than pathogen-derived factors are involved in the regulation of Notch ligand expression in dendritic cells (DCs) remains unknown. Here, we address the effect of T helper cells (Th1 and Th2) on Delta-like 4 and Jagged 2 expression in bone marrow-derived DCs. We demonstrate that both Th1 and Th2 cells induce Delta-like 4 mRNA expression in DCs, in a process that is, in part, mediated by CD40 signalling. In contrast, only Th2 cells induce a significant increase in Jagged 2 mRNA levels in DCs. Additionally, we show that IL-4, a hallmark Th2 cytokine, plays a role in Jagged 2 expression, as evidenced by the fact that cholera toxin, a Th2-promoting stimulus, induces Jagged 2 mRNA expression in DCs only in the presence of IL-4. Finally, we demonstrate that DCs also express Notch 1 and that this expression is downregulated by IL-4. These data suggest that Notch ligands are differentially regulated in DCs: Delta-like 4 is regulated by T helper cells and by pathogen-derived Th1 stimuli, whereas Jagged 2 is regulated by Th2 cells and pathogen-derived Th2-promoting stimuli. Based on our results, we propose that the positive feedback loop that Th2 cells exert on T cell polarization may involve the induction of Jagged 2 expression in DCs.
authors.affiliation: Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.
authors.forename: D
authors.initials: D
authors.lastname: Sauma
authors.forename: P
authors.initials: P
authors.lastname: Espejo
authors.forename: A
authors.initials: A
authors.lastname: Ramirez
authors.forename: A
authors.initials: A
authors.lastname: Fierro
authors.forename: M
authors.initials: M
authors.lastname: Rosemblatt
authors.forename: M R
authors.initials: MR
authors.lastname: Bono
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019013:CD40 Antigens / Q000276:immunology; D002135:Calcium-Binding Proteins; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D054884:Host-Pathogen Interactions / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D000072101:Jagged-2 Protein; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019013:CD40 Antigens; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; C490503:Jag2 protein, mouse; D000072101:Jagged-2 Protein; D008565:Membrane Proteins; D015847:Interleukin-4