Human immature myeloid dendritic cells trigger a TH2-polarizing program via Jagged-1/Notch interaction.
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.
Liotta
Francesco
F
Excellence Center for Research, Transfer, and High Education, De Novo Therapy, University of Florence, Florence, Italy.
Frosali
Francesca
F
Querci
Valentina
V
Mantei
Andrej
A
Filì
Lucia
L
Maggi
Laura
L
Mazzinghi
Benedetta
B
Angeli
Roberta
R
Ronconi
Elisa
E
Santarlasci
Veronica
V
Biagioli
Tiziana
T
Lasagni
Laura
L
Ballerini
Clara
C
Parronchi
Paola
P
Scheffold
Alexander
A
Cosmi
Lorenzo
L
Maggi
Enrico
E
Romagnani
Sergio
S
Annunziato
Francesco
F
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
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