title: Human immature myeloid dendritic cells trigger a TH2-polarizing program via Jagged-1/Notch interaction.
abstract: BACKGROUND
  The mechanisms by which human dendritic cells (DCs) activate a TH1-polarizing or TH2-polarizing program are still partially unclear.
  
  
  OBJECTIVE
  Study of the mechanisms responsible for the TH1/TH2-polarizing activity of human circulating myeloid DCs before and after ligation of their Toll-like receptors (TLRs).
  
  
  METHODS
  IL-4 and IFN-gamma production by CD4+ T cells was assessed in cocultures with myeloid DCs before or after TLR triggering. Expression of Jagged-1 and Delta-4 Notch ligands and of GATA-3 and T-box expressed in T cells transcription factors was evaluated by real-time quantitative PCR. Signal transducer and activator of transcription 4 and 6 phosphorylation was assessed by flow cytometry. Knockdown of Jagged-1 or Delta-4 was performed by transfection of DCs with appropriate silencing mRNAs.
  
  
  RESULTS
  Myeloid immature DCs constitutively expressed Jagged-1, which induces in CD4+ T cells a TH2 polarization, as shown by Jagged-1 gene silencing. The TH2 polarization associated with high GATA-3/T-box expressed in T cells ratio and was at least partially dependent on the early induction of IL-4. Maturation of DCs by TLR ligation resulted in the reduction of Jagged-1 and upregulation of Delta-4, which was at least in part responsible for the polarization of CD4+ T cells to the TH1 phenotype.
  
  
  CONCLUSIONS
  CD4+ T-cell responses are usually characterized by a prevalent TH2 phenotype unless TLRs are triggered on DCs by microbial components.
authors.affiliation: Excellence Center for Research, Transfer, and High Education, De Novo Therapy, University of Florence, Florence, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Liotta
authors.forename: Francesca
authors.initials: F
authors.lastname: Frosali
authors.forename: Valentina
authors.initials: V
authors.lastname: Querci
authors.forename: Andrej
authors.initials: A
authors.lastname: Mantei
authors.forename: Lucia
authors.initials: L
authors.lastname: Filì
authors.forename: Laura
authors.initials: L
authors.lastname: Maggi
authors.forename: Benedetta
authors.initials: B
authors.lastname: Mazzinghi
authors.forename: Roberta
authors.initials: R
authors.lastname: Angeli
authors.forename: Elisa
authors.initials: E
authors.lastname: Ronconi
authors.forename: Veronica
authors.initials: V
authors.lastname: Santarlasci
authors.forename: Tiziana
authors.initials: T
authors.lastname: Biagioli
authors.forename: Laura
authors.initials: L
authors.lastname: Lasagni
authors.forename: Clara
authors.initials: C
authors.lastname: Ballerini
authors.forename: Paola
authors.initials: P
authors.lastname: Parronchi
authors.forename: Alexander
authors.initials: A
authors.lastname: Scheffold
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Cosmi
authors.forename: Enrico
authors.initials: E
authors.lastname: Maggi
authors.forename: Sergio
authors.initials: S
authors.lastname: Romagnani
authors.forename: Francesco
authors.initials: F
authors.lastname: Annunziato
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism* / Q000502:physiology; D002450:Cell Communication / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D050990:GATA3 Transcription Factor / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D016130:Immunophenotyping; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism* / Q000502:physiology; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000378:metabolism* / Q000502:physiology; D023461:Myeloid Progenitor Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism* / Q000502:physiology; D000072099:Serrate-Jagged Proteins; D020825:T-Box Domain Proteins / Q000096:biosynthesis / Q000235:genetics; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D000098815:T-bet Transcription Factor
chemical_list: D002135:Calcium-Binding Proteins; D050990:GATA3 Transcription Factor; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor