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 T(H)1-polarizing or T(H)2-polarizing program are still partially unclear. Objective: Study of the mechanisms responsible for the T(H)1/T(H)2-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 T(H)2 polarization, as shown by Jagged-1 gene silencing. The T(H)2 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 T(H)1 phenotype. Conclusion: CD4(+) T-cell responses are usually characterized by a prevalent TH2 phenotype unless TLRs are triggered on DCs by microbial components.