DLL4⁺ dendritic cells: Key regulators of Notch Signaling in effector T cell responses

Dendritic cells (DCs) are critical regulators of adaptive immune responses. DCs can elicit primary T cell responses at low DC:T cell ratios through their expression of high levels of antigen-presenting molecules and costimulatory molecules. DCs are important for induction of functionally diverse T cell subsets such as CD4⁺ T helper (Th)1 and Th17 cells and effector CD8⁺ T cells able to reside in epithelial tissues. Recent studies begin illuminating the underlying mechanism by which DCs regulate specialized T cell subsets. DCs are composed of subsets that differ in their phenotype, localization and function. DCs expressing high levels of DLL4 (DLL4⁺ DCs), which is a member of Notch ligand family, are newly discovered cells that have greater ability than DLL4^- DCs to promote the generation of Th1 and Th17 CD4⁺ T cells. DLL4 derived from DLL4⁺ DCs is also important for promoting the differentiation and expansion of effector CD8⁺ T cells. Experimental studies have demonstrated that selective deletion of DLL4 in DCs causes impaired antitumor immunity. In contrast, blocking DLL4 leads to dramatic reduction of inflammatory T cell responses and their-mediated tissue damage. We will discuss emerging functional specialization within the DLL4⁺ DC compartment, DLL4⁺ DC biology and the impact of pharmacological modulation of DLL4 to control inflammatory disorders.