Abstract
The Notch pathway plays a role in the processes of cell proliferation, differentiation, and apoptosis, which affect the development and function of various organs. Dendritic cells (DCs), as professional antigen-presenting cells (APCs), induce T cell activation and promote T cell differentiation by antigen stimulation. Research has shown that Notch ligand delta-like 4 (Dll4) in APCs is associated with stimulation of a Th1-type response. However, the regulatory roles of Dll4 in the activation and function of DCs have yet to be clearly elucidated. In this study, we demonstrated that activation of Dll4-pretreated bone marrow-derived DCs by performing ovalbumin (OVA) stimulation expressed a high level of interleukin (IL)-10 without diminishing IL-12 production. By contrast, the proinflammatory cytokines, IL-1β, IL-6, and tumor necrosis factor (TNF)-α, decreased in Dll4-pretreated DCs by performing either lipopolysaccharide (LPS) or OVA stimulation. Compared to fully mature DCs, lower levels of MHC class II CD40 and higher levels of CD80 and CD86 molecules were expressed in these semi-mature like DCs. Dll4 Notch signaling also enhanced Notch ligand mRNA expression of Dll1, Dll4, and Jagged1 in DCs. Dll4-modified DCs exhibited a reduced capacity to stimulate the proliferation of OVA-specific CD4+ T cells, but actively promoted large amounts of IL-10 production in these activated T cells. Furthermore, immunomodulatory effects of Dll4-modified DCs were examined in an established asthmatic animal model. After adoptive transfer of OVA-pulsed plus Dll4-pretreated DCs in OVA-immunized mice, OVA challenge induced lower OVA-specific immunoglobulin E (IgE) and higher IgG2a antibody production, lower eotaxin, keratinocyte-derived chemokine (KC), IL-5, and IL-13 release in bronchial alveolar lavage fluid, attenuated airway hyper-responsiveness, and promoted higher IL-10 and interferon (IFN)-γ production in the spleen. In summary, our findings elucidate the new role of Dll4 in the phenotype and function of DCs and provide a novel approach for manipulating T cell-driven deleterious immune diseases.
Highlights
Dendritic cells (DCs) are the most potent antigen (Ag)presenting cells (APCs) of the immune system and are critically involved in initiating primary immune responses and inducing T cell responses
Before testing the effects of delta-like 4 (Dll4) on mouse bone-marrowderived DCs (BMDCs), we examined the effects of Dll4 protein on cell viability
We addressed the impact of Dll4 on the production of IL-10 and IL-12 cytokines by DCs
Summary
Dendritic cells (DCs) are the most potent antigen (Ag)presenting cells (APCs) of the immune system and are critically involved in initiating primary immune responses and inducing T cell responses. Immature DCs display the highest capacity to internalize Ags but are poor T-cell activators. After Ag uptake, DCs mature, become specialized in Ag presentation, and are excellent T-cell stimulators. Maturation of DCs can be triggered by components of the bacterial wall, proinflammatory cytokines, and viral components [1]. As mature APCs, DCs display longlasting peptide-MHC class II complexes on the surface and upregulate surface levels of co-stimulatory molecules (CD40, CD80, and CD86) and intercellular adhesion molecules (CD54). Mature DCs produce high levels of interleukin (IL)-
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