Jagged1-expressing adenovirus-infected dendritic cells induce expansion of Foxp3+ regulatory T cells and alleviate T helper type 2-mediated allergic asthma in mice
Jagged1-expressing adenovirus-infected dendritic cells induce expansion of Foxp3+ regulatory T cells and alleviate T helper type 2-mediated allergic asthma in mice
复制标题
DOI：
10.1111/imm.13021
复制
发表时间：
2019-02-01
期刊：
影响因子：
6.4
通讯作者：
Lee, Yueh-Lun
中科院分区：
文献类型：
--
作者：
Lin, Chu-Lun;Huang, Huei-Mei;Lee, Yueh-Lun
树突状细胞（Dendritic cells，DC）是专职的抗原呈递细胞，在指导T细胞应答中起关键作用。调节性T（Treg）细胞具有抑制效应T细胞应答的免疫抑制能力，并且Notch配体Jagged 1（Jag 1）涉及Treg细胞分化。在这项研究中，我们评估是否骨髓来源的DCs基因工程表达Jag 1（Jag 1-DCs）会影响在体外的DCs的成熟和功能，并进一步研究Jag 1-DCs的免疫调节能力，以操纵辅助性T细胞2型（Th 2）介导的过敏性哮喘小鼠。我们通过腺病毒转导产生Jag 1-DCs。卵清蛋白（OVA）刺激的Jag 1-DCs过表达Jag 1表现出程序性细胞死亡配体1（PD-L1）和OX 40 L分子表达增加。随后，将这些OVA脉冲的Jag 1-DC与同种异体或同基因的CD 4（+）T细胞共培养促进Foxp 3（+）Treg细胞的产生，并且使用特异性抗体阻断PD-L1部分减少Treg细胞扩增。此外，过继转移OVA脉冲的Jag 1-DCs与OVA诱导的哮喘小鼠减少过敏原特异性免疫球蛋白E的生产，气道高反应性，气道炎症，和分泌的Th 2型细胞因子（白细胞介素-4，白细胞介素-5，白细胞介素-13）。值得注意的是，在Jag 1-DC处理的小鼠中观察到Foxp 3（+）Treg细胞数量增加，与转化生长因子-β产生水平增加相关。这些数据表明DCs转基因表达Jag 1可促进Foxp 3（+）Treg细胞的诱导，从而改善小鼠Th 2介导的过敏性哮喘。我们的研究支持一个有吸引力的策略，人工产生免疫调节DC，并提供了一种新的方法来操纵Th 2细胞驱动的有害免疫疾病。
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-beta 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.