Jagged1 on Dendritic Cells and Notch on CD4+ T Cells Initiate Lung Allergic Responsiveness by Inducing IL-4 Production

Abstract

Jagged1, a Notch ligand, and Notch have been implicated in Th2 differentiation, but their role in initiating IL-4 production and Th2 differentiation in vivo and the development of allergic airway responses has not been defined. In this study, we show that Jagged1 is up-regulated on bone marrow-derived dendritic cells (BMDCs) pulsed with allergen and that the transfer of these BMDCs before allergen challenge induces airway hyperresponsiveness (AHR) and eosinophilic airway inflammation. Treatment of CD4+ T cells with a γ-secretase inhibitor (GSI), which inhibits Notch signaling, resulted in decreased cytokine production when the cells were cocultured with allergen-pulsed, Jagged1-expressing BMDCs and, after the transfer of allergen-pulsed BMDCs, IL-4-deficient (IL-4−/−) recipients of GSI-treated naive CD4+ T cells developed lower levels of AHR, reduced numbers of eosinophils, and lower Th2 cytokine levels when challenged with allergen. In vivo treatment of wild-type mice with Jagged1-Fc enhanced AHR and airway inflammation, whereas the transfer of BMDC transfected with Jagged1 small interfering RNA (siRNA) cells into WT or IL-4−/− mice before transfer of CD4+ T cells resulted in decreased AHR, inflammation, and Th2 cytokines, indicating the critical role for Jagged1 expression on APCs. These data identify the essential role of the interactions between Notch on CD4+ T cells and Jagged1 on APCs in the initiation of IL-4 production and Th2 differentiation for the development of AHR and allergic airway inflammation.

NK Cell Deficiency Predisposes to Viral-Induced Th2-Type Allergic Inflammation via Epithelial-Derived IL-25

“…Jagged1 expression on DCs can polarize both human (38) and mouse (39) T cells to the Th2 phenotype independently of IL-4. Furthermore, treatment of mice with Jagged1-Fc fusion protein has been shown to enhance inflammation in a model of allergic airways disease (39). Our data reveal an important role for IL-25 in the regulation of Jagged1 expression on mediastinal lymph node DCs that significantly contributes to the generation of viral-induced Th2 responses.…”

Contribution of a Streptococcus mutans Antigen Expressed by a Salmonella Vector Vaccine in Dendritic Cell Activation

“…BRD509(pSBRT7)-stimulated DC showed increased Jagged-1 expression over that induced by BRD509-stimulated DC. The Notch ligands Delta-1 and Jagged-1 have been shown to selectively induce Th1 or Th2 differentiation (3,33,38); thus, we wanted to determine if signaling via these molecules could shed some light on the cytokine pattern. Induction of Jagged-1 expression occurred after 12, 24, and 48 h of stimulation of DC with BRD509(pSBRT7) or BRD509 (Fig.…”

Ligation of Notch Receptors in Human Conventional and Plasmacytoid Dendritic Cells Differentially Regulates Cytokine and Chemokine Secretion and Modulates Th Cell Polarization

“…Cellular activation alters the expression of Notch molecules on DCs, which modifies Th cell polarization (32,35,36). Additionally, Notch signaling itself is also involved in activation of DCs, as ligand binding induced upregulation of MHC class II (MHC-II), CD80, CD83, and CD86, production of different cytokines, and higher levels of T cell proliferation (37)(38)(39).…”