Study on the Immuno-Modulatory Effects of Notch Ligand Delta 4 on Immune Cells and in Ova-Induced Asthmatic Mice

Allergic asthma is characterized by airway hyperresponsiveness (AHR) to specific and non-specific stimuli with elevated serum IgE levels and eosinophilic inflammation. It is well known that generation of allergen-specific CD4+ type 2, T-helper (Th2) cells are the most important prerequisites for the development of allergic asthma. Thus far, one of therapeutic strategies that induce Th1 responses seems to have the greatest potential to inhibit allergen-induced disorders. Vaccines inducing type 1, T-helper cells (Th1) responses may prove successful in inhibiting allergic Th2 responses and Notch ligands are considered especially good candidates for the role. Therefore, we aim to explore the ability and regulatory mechanism of Notch ligand Delta4 in the induction of immune cells maturation and differentiation, and the effects of Delta4-transduced DCs in the murine model of asthma. The following hypotheses will be tested: Hypothesis 1: The activation of Notch signaling by Notch ligand Delta4 binding on immature dendritic cells (DCs) can affect the activation and maturation of DCs by nuclear transcription factor NF-κB pathway. (1st year) 1.1: Plate-bound Delta4 enhances the expression of Delta ligands in DCs. 1.2: Plate-bound Delta4 induces a distinctive maturation profile in DCs. 1.3: Delta4 induces DCs maturation through NF-κB pathway. 1.4: Delta4-treated DCs modulate the differentiation of activated CD4+ T cells. Hypothesis 2: Notch ligand Delta4 and Notch1 receptor interaction promotes Th1 development and Hes1 binding STAT4 mediates crosstalk between Notch and STAT signaling. (2nd year) 2.1: Plate-bound Delta4 facilitates Th cells priming. 2.2: Plate-bound Delta4 promotes secretion of IFN-γ and upregulates the expression of T-bet in Th cells. 2.3: Delta4 and Notch1 interaction promotes Th1 development. 2.4: Hes1 (Hairy/Enhancer of split) binding STAT4 (Signal Transducers and Activators of Transcription-4) mediates crosstalk between Notch and STAT signaling. 2.5: Delta4-transduced DCs promote Th1 cell development in vitro. Hypothesis 3: The injection of Delta4-transduced DCs may prevent the development of Th2 cells or reverse established Th2 response in a murine asthma model. (3rd year) We believe that our project might shed light further understanding the regulatory mechanisms of DCs, in particular in the area of CD4+ T-cell polarization, and ultimately result in DC-based vaccines to prevent the development of (or inhibit established) atopic asthma.