Laboratory of Immune Regulation, Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea; BK21 Plus Program, College of Pharmacy, Seoul National University, Seoul, Korea.
Laboratory of Immune Regulation, Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea.
J Allergy Clin Immunol. 2018 Jun;141(6):2061-2073.e5. doi: 10.1016/j.jaci.2017.07.050. Epub 2017 Sep 22.
Allergic asthma is a heterogeneous chronic inflammatory disease of the airways with a massive infiltration of eosinophils or neutrophils mediated by allergen-specific T2 and T17 cells, respectively. Therefore successful treatment of allergic asthma will require suppression of both T2 and T17 cells.
We sought to investigate the role of the T17 cell pathway in regulating T2 cell responses in allergic asthma.
Allergic asthma was induced by intranasal challenge with proteinase allergens in C57BL/6, Il17aIl17f, and retinoic acid receptor-related orphan receptor γt (RORγt) 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.
Mice deficient in IL-17A and IL-17F, as well as RORγt, exhibited a significant reduction not only in T17 cell responses but also in T2 cell responses in an animal model of allergic asthma. Similarly, mice treated with an RORγt inhibitor had significantly diminished T17 and T2 cell responses, leading to reduced neutrophil and eosinophil numbers in the airway. RORγt-deficient T cells were intrinsically defective in differentiating into T2 cells and expressed increased levels of B-cell lymphoma 6 (Bcl6). Bcl6 knockdown resulted in a remarkable restoration of T2 cell differentiation in RORγt-deficient T cells. Blockade of RORγt also significantly hampered the differentiation of human T2 and T17 cells from naive CD4 T cells.
RORγt in T cells is required for optimal T2 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 T17 and T2 cell responses in the airway.
过敏性哮喘是一种气道慢性炎症性疾病，其特征为嗜酸性粒细胞或中性粒细胞大量浸润，分别由过敏原特异性 T2 和 T17 细胞介导。因此，成功治疗过敏性哮喘需要抑制 T2 和 T17 细胞。
我们旨在研究 T17 细胞通路在调节过敏性哮喘中 T2 细胞反应中的作用。
采用蛋白酶过敏原经鼻内激发建立 C57BL/6、Il17aIl17f 和维甲酸受体相关孤儿受体 γt（RORγt）小鼠过敏性哮喘模型。采用 RORγt 药理学抑制剂评估其在过敏性哮喘中的预防和治疗作用。采用流式细胞术、组织学、实时定量 PCR 和 ELISA 分析过敏性气道炎症特征。采用混合骨髓嵌合体小鼠、谱系追踪分析、短发夹 RNA 转导和体外 T 细胞分化进行机制研究。
IL-17A 和 IL-17F 缺陷以及 RORγt 缺陷的小鼠，不仅 T17 细胞反应，而且在过敏性哮喘动物模型中 T2 细胞反应均显著减少。同样，用 RORγt 抑制剂治疗的小鼠，T17 和 T2 细胞反应明显减少，导致气道中中性粒细胞和嗜酸性粒细胞数量减少。RORγt 缺陷的 T 细胞在分化为 T2 细胞方面存在固有缺陷，并且表达较高水平的 B 细胞淋巴瘤 6（Bcl6）。Bcl6 敲低导致 RORγt 缺陷的 T 细胞中 T2 细胞分化显著恢复。阻断 RORγt 也显著阻碍了人 T2 和 T17 细胞从幼稚 CD4 T 细胞分化。
T 细胞中的 RORγt 通过抑制 Bcl6 表达促进 T2 细胞分化，这表明靶向 RORγt 可能是通过同时抑制气道中 T17 和 T2 细胞反应来治疗过敏性哮喘的一种有前途的方法。
