Cutting edge: Plasmacytoid dendritic cells induce IL-10 production in T cells via the Delta-like-4/Notch axis.

Proinflammatory Th1 cells can produce large amounts of the immunosuppressive cytokine IL-10, thereby facilitating the self-limitation of inflammatory responses. Recently, we identified the Notch pathway as a main regulator of IL-10 production by Th1 cells. In this study, we show that plasmacytoid dendritic cells (pDCs), by means of their unique high-level expression of the Notch ligand Delta-like (Dll)-4, activate the Notch receptor on T cells to induce robust IL-10 production in vitro and in vivo. pDCs display a distinct pattern of Notch ligands compared with conventional dendritic cells, marked by the constitutive expression of Dll-4, the only Notch ligand to induce IL-10 expression in vivo, and Dll-1, while at the same time lacking the expression of Jagged. We provide a new mechanism for IL-10 induction by pDCs underlining the importance of the Dll-4/Notch axis in the regulation of inflammatory T cell responses.

Notch regulates IL-10 production by T helper 1 cells.

T helper 1 (Th1) cells mediate powerful cellular immune responses. However, if unbalanced, Th1 immunity eventually may cause pathology. Recently, it has been shown that IL-10, an antiinflammatory cytokine strongly antagonizing Th1-mediated effects, can be produced by Th1 cells and is indeed essential for self-regulation of Th1 immunity. Here, we show that Notch induces IL-10 production in newly developing and already established Th1 cells via a signal transducer and activator of transcription 4 (STAT4)-dependent process. Notch signaling in the presence of the cytokines IL-12 or IL-27 induces Th1 cells to produce large amounts of IL-10 without diminishing IFN-gamma production. Notch-modified Th1 cells completely lose their inflammatory capacity and instead are able to actively suppress a Th1 cell-induced delayed-type hypersensitivity (DTH) reaction in an IL-10-dependent fashion. IL-10 production can be elicited by active forms of all four mammalian Notch receptors but was found to be specific for the Delta-like family of Notch ligands. Dendritic cells (DC) selectively acquire Delta-like 4 expression upon stimulation with various Toll-like receptor (TLR) ligands and concomitantly induce IL-10 production by Th1 cells in vitro and in vivo. This effect can be selectively reversed by pharmacological inhibitors of Notch signaling (gamma-secretase inhibitor). Our data suggest that Notch regulates IL-10 production in Th1 cells by a STAT4-dependent process that converts proinflammatory Th1 cells into T cells with regulatory activity. This pathway may provide unique opportunities for therapeutic intervention in Th1-driven immune diseases and for Th1-associated vaccination strategies.