Notch ligand Delta-like 4 regulates development and pathogenesis of allergic airway responses by modulating IL-2 production and Th2 immunity (141.15)

Abstract

Abstract Activation of the conical Notch pathways have been implicated in Th cell differentiation, but the role of specific Notch ligands in Th2 mediated allergic airway responses has not been completely elucidated. In this study, we show that delta-like 4 (Dll4) was up-regulated on dendritic cells in response to cockroach allergen. Blocking Dll4 in vivo at either the afferent or efferent phases of the immune response enhanced allergen-induced pathogenic responses including airway hyperresponsiveness (AHR) and mucus production via increased Th2 cytokines. In vitro assays demonstrated that Dll4 regulates IL-2 in T cells from established Th2 responses as well as during primary stimulation. Interestingly, Dll4 blockade during the afferent, but not the efferent phase, increased IL-2 levels in lung and lymph node of allergic mice. Moreover, Dll4-mediated Notch activation of T cells during primary stimulation in vitro increased apoptosis during the contraction/resting phase of the response, which could be rescued by exogenous IL-2. Consistent with the role for Dll4-mediated IL-2 regulation in overall T cell function, the frequency of IL-4 producing cells were also significantly altered by Dll4 both in vivo and in vitro. These data demonstrate a regulatory role of Dll4 on both Th2 differentiation as well as on Th2 cytokine production in established Th2 responses.