Interleukin-38-overexpressing adenovirus infection in dendritic cell-based treatment enhances immunotherapy for allergic asthma via inducing Foxp3+ regulatory T cells

Abstract

Allergic asthma is a chronic disease tied to unusual immune reactions involving type 2 T helper (Th2) cells specific to allergens. Dendritic cells (DCs) play a crucial role in guiding T-cell responses. Regulatory T (Treg) cells have the ability to suppress effector T-cell responses, and interleukin (IL)-38 is involved in Treg cell differentiation. In this study, we explored impacts of IL-38 on the activation and function of DCs, and we then developed an IL-38-overexpressing adenovirus (Ad-IL38) to evaluate its effectiveness in treating allergic asthma in mice through the adaptive transfer of Ad-IL38-infected DCs (IL38-DCs). Treating lipopolysaccharide (LPS)-activated bone marrow-derived DCs with recombinant IL-38 reduced cluster of differentiation 80 (CD80), CD86, and major histocompatibility complex (MHC) II expressions and decreased IL-1β, IL-6, and tumor necrosis factor (TNF)-α while increasing IL-10 secretion. The simultaneous culture of these semi-mature DCs with allogeneic CD4⁺ T cells facilitated the production of Forkhead box protein P3-positive (Foxp3⁺) Treg cells. A transcriptomic analysis revealed downregulation of the Chil3, Inhba, and Ctgf genes that are crucial for regulating inflammatory responses and cytokine-mediated signaling pathways in IL-38-treated DCs. In an animal model of asthma, IL38-DC treatment effectively decreased levels of an ovalbumin (OVA)-specific immunoglobulin E (IgE) antibody in serum, attenuated the severity of airway hyperresponsiveness, reduced the production of Th2-type cytokines (IL-4, IL-5, and IL-13) and proinflammatory cytokines (IL-6 and TNF-α) in bronchoalveolar lavage fluid, lowered expressions of the Th2-related cytokines IL-25 and thymic stromal-derived lymphopoietin (TSLP) by lung epithelial cells, and mitigated airway inflammation. Notably, enhanced expression of Foxp3⁺ Treg cells was linked to increased mRNA levels of transforming growth factor (TGF)-β production in vivo. In conclusion, we comprehensively clarified the immunomodulatory effects of IL-38 on DCs and provide a new treatment with IL-38 genetically modified DCs for alleviating Th2-mediated allergic diseases.

Keywords: Adenovirus; Allergic asthma; Dendritic cell; Interleukin-38; T cell.