Regulation of T cell activation by Notch ligand, DLL4, promotes IL-17 production and Rorc activation.

The activation and differentiation of T cells are dependent upon numerous initiating events that are influenced by the immune environment, nature of the Ag, as well as the activation state of APCs. In the present studies we have investigated the role of a specific notch ligand, delta-like 4 (Dll4). In particular, our data have indicated that Dll4 is inducible by pathogen-associated signals through TLR activation on dendritic cells but not early response inflammatory cytokines, IL-1 and IL-18 that also activate cells via MyD88 adapter pathway. Our observations from in vitro cultures confirmed earlier reports demonstrating that Dll4 inhibits Th2 cytokine production. Furthermore, Dll4 influences the generation of IL-17-producing T cells in the presence of additional skewing cytokines, IL-6 and TGF-beta. In the absence of notch signals, IL-17 production was significantly inhibited even under specific skewing conditions. These studies further demonstrate that Dll4 up-regulates Rorc expression in T cells and that both Rorc and Il17 gene promoters are direct transcriptional notch targets that further enhance the differentiation of Th17 cell populations. Thus, facilitation of efficient T cell differentiation may depend upon the activation of T cells via specific notch ligand stimulation.