Jagged1‐expressing adenovirus‐infected dendritic cells induce expansion of Foxp3⁺ regulatory T cells and alleviate T helper type 2‐mediated allergic asthma in mice

Abstract

Summary Dendritic cells (DCs) are professional antigen‐presenting cells that play a key role in directing T‐cell responses. Regulatory T (Treg) cells possess an immunosuppressive ability to inhibit effector T‐cell responses, and Notch ligand Jagged1 (Jag1) is implicated in Treg cell differentiation. In this study, we evaluated whether bone marrow‐derived DCs genetically engineered to express Jag1 (Jag1‐DCs) would affect the maturation and function of DCs in vitro and further investigated the immunoregulatory ability of Jag1‐DCs to manipulate T helper type 2 (Th2) ‐mediated allergic asthma in mice. We produced Jag1‐DCs by adenoviral transduction. Overexpression of Jag1 by ovalbumin (OVA) ‐stimulated Jag1‐DCs exhibited increased expression of programmed cell death ligand 1 (PD‐L1) and OX40L molecules. Subsequently, co‐culture of these OVA‐pulsed Jag1‐DCs with allogeneic or syngeneic CD4+ T cells promoted the generation of Foxp3+ Treg cells, and blocking PD‐L1 using specific antibodies partially reduced Treg cell expansion. Furthermore, adoptive transfer of OVA‐pulsed Jag1‐DCs to mice with OVA‐induced asthma reduced allergen‐specific immunoglobulin E production, airway hyperresponsiveness, airway inflammation, and secretion of Th2‐type cytokines (interleukin‐4, interleukin‐5, and interleukin‐13). Notably, an increased number of Foxp3+ Treg cells associated with enhanced levels of transforming growth factor‐β production was observed in Jag1‐DC‐treated mice. These data indicate that transgenic expression of Jag1 by DCs promotes induction of Foxp3+ Treg cells, which ameliorated Th2‐mediated allergic asthma in mice. Our study supports an attractive strategy to artificially generate immunoregulatory DCs and provides a novel approach for manipulating Th2 cell‐driven deleterious immune diseases.

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Notch ligand-expressing adenovirus infection enhances the efficacy of dendritic cell-based immunotherapy for allergic asthma in mice

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