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

摘要

Activation of the canonical Notch pathways has 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 during either the primary or secondary response enhanced allergen-induced pathogenic consequences 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 primary, but not the secondary response, increased IL-2 levels in lung and lymph node of allergic mice. The in vivo neutralization of Dll4 was associated with increased expansion and decreased apoptosis during the primary allergen sensitization. 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 initial Th2 differentiation as well as on Th2 cytokine production in established allergic responses.