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-γ 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 T H 2 phenotype unless TLRs are triggered on DCs by microbial components.