The activation and differentiation of T cells are dependent upon numerous initiating events that are influenced by the immune environment, nature of the antigen, as well as the activation state of APCs. The study evaluated how activation by a specific notch ligand, delta-like 4 (DLL4), expressed by dendritic cells relates to the development of specific aspects of T cell differentiation. In particular, our data have indicated that DLL4 is inducible by pathogen-associated signals through TLR activation but not by early response inflammatory cytokines, IL-1 and IL-18 that also activate cells via MyD88 adapter molecules. To investigate the ability of Dll4 to activate T cells, our observations from in vitro specific cultures with ovalbumin peptide specific TCR transgenic cells (DO11.10) confirmed earlier reports that Dll4 inhibits Th2 cytokine production but further indicated that it also influences the generation of IL-17 producing T cells. However additional skewing conditions were necessary to drive IL17 production. In the absence of notch signals IL17 production was significantly inhibited. We also identified that both RORγt and IL17 are direct transcriptional notch targets that further enhance the differentiation of Th17 cell populations. Thus, the regulation of T cell differentiation may depend upon the efficient activation of T cells by specific notch ligand stimulation by novel activation pathways.

Acknowledgement: This work was supported by the NIH RO1-AI073876 grant to Nicholas W. Lukacs.