BACKGROUND Allergic asthma is a heterogeneous chronic inflammatory disease of the airways with a massive infiltration of eosinophils or neutrophils mediated by allergen-specific TH2 and TH17 cells, respectively. Therefore successful treatment of allergic asthma will require suppression of both TH2 and TH17 cells. OBJECTIVE We sought to investigate the role of the TH17 cell pathway in regulating TH2 cell responses in allergic asthma. METHODS Allergic asthma was induced by intranasal challenge with proteinase allergens in C57BL/6, Il17a-/-Il17f-/-, and retinoic acid receptor-related orphan receptor γt (RORγt)gfp/gfp mice. A pharmacologic RORγt inhibitor was used to evaluate its preventive and therapeutic effects in allergic asthma. Characteristics of allergic airway inflammation were analyzed by using flow cytometry, histology, quantitative real-time PCR, and ELISA. Mixed bone marrow chimeric mice, fate mapping analysis, short hairpin RNA transduction, and in vitro T-cell differentiation were used for mechanistic studies. RESULTS Mice deficient in IL-17A and IL-17F, as well as RORγt, exhibited a significant reduction not only in TH17 cell responses but also in TH2 cell responses in an animal model of allergic asthma. Similarly, mice treated with an RORγt inhibitor had significantly diminished TH17 and TH2 cell responses, leading to reduced neutrophil and eosinophil numbers in the airway. RORγt-deficient T cells were intrinsically defective in differentiating into TH2 cells and expressed increased levels of B-cell lymphoma 6 (Bcl6). Bcl6 knockdown resulted in a remarkable restoration of TH2 cell differentiation in RORγt-deficient T cells. Blockade of RORγt also significantly hampered the differentiation of human TH2 and TH17 cells from naive CD4+ T cells. CONCLUSION RORγt in T cells is required for optimal TH2 cell differentiation by suppressing Bcl6 expression; this finding suggests that targeting RORγt might be a promising approach for the treatment of allergic asthma by concomitantly suppressing TH17 and TH2 cell responses in the airway.

中文翻译：

---

以视黄酸受体相关的孤儿受体γt为靶点，同时抑制过敏性哮喘中TH2和TH17细胞的应答。

背景技术变应性哮喘是气道的异质性慢性炎性疾病，其分别由变应原特异性TH2和TH17细胞介导的嗜酸性粒细胞或嗜中性粒细胞大量浸润。因此，成功治疗过敏性哮喘将需要同时抑制TH2和TH17细胞。目的我们试图研究TH17细胞途径在过敏性哮喘中调节TH2细胞反应的作用。方法C57BL / 6，Il17a-/-Il17f-/-和视黄酸受体相关的孤儿受体γt（RORγt）gfp / gfp小鼠鼻内用蛋白酶过敏原激发可引起过敏性哮喘。使用药理学的RORγt抑制剂评估其在过敏性哮喘中的预防和治疗作用。使用流式细胞仪，组织学，定量实时PCR和ELISA。混合骨髓嵌合小鼠，命运映射分析，短发夹RNA转导和体外T细胞分化用于机制研究。结果在过敏性哮喘动物模型中，缺乏IL-17A和IL-17F以及RORγt的小鼠不仅表现出TH17细胞应答的显着降低，而且表现出TH2细胞应答的显着降低。同样，用RORγt抑制剂治疗的小鼠可显着降低TH17和TH2细胞反应，从而导致气道中性粒细胞和嗜酸性粒细胞减少。缺乏RORγt的T细胞在分化为TH2细胞方面本质上存在缺陷，并且表达的B细胞淋巴瘤6（Bcl6）水平升高。Bcl6敲低导致RORγt缺陷T细胞中TH2细胞分化的显着恢复。RORγt的阻滞也显着阻碍了人类TH2和TH17细胞从幼稚CD4 + T细胞的分化。结论T细胞中的RORγt是通过抑制Bcl6表达来实现TH2细胞最佳分化的必需条件。该发现表明，通过同时抑制气道中的TH17和TH2细胞反应，靶向RORγt可能是治疗变应性哮喘的一种有前途的方法。