Abstract：
BACKGROUND: Asthma is often accompanied by type 2 immunity rich in IL-4, IL-5 and IL-13 cytokines produced by TH2 lymphocytes or type 2 innate lymphoid cells (ILC2s). Interleukin-2 family cytokines play a key role in the differentiation, homeostasis and effector function of innate and adaptive lymphocytes.
OBJECTIVE: IL-9 and IL-21 boost the activation and proliferation of TH2 and ILC2s, but the relative importance and potential synergism between these γc cytokines is currently unknown.
METHODS: Using newly generated antibodies, we inhibited IL-9 and IL-21 alone or in combination, in various murine models of asthma. In a translational approach using segmental allergen challenge, we recently described elevated IL-9 levels in human allergic asthmatics in comparison to non-asthmatic controls. Here, we also measured IL-21 in both groups.
RESULTS: IL-9 played a central role in controlling innate IL-33 induced lung inflammation by promoting proliferation and activation of ILC2s, in an IL-21 independent manner. Conversely, chronic house dust mite induced airway inflammation, mainly driven by adaptive immunity, was solely dependent on IL-21, that controlled TH2 activation, eosinophilia, total serum IgE and formation of tertiary lymphoid structures. In a model of innate on adaptive immunity driven by papain allergen, a clear synergy was found between both pathways, since combined anti-IL-9 or anti-IL-21 blockade was superior in reducing key asthma features. In human bronchoalveolar lavage (BAL) samples we measured elevated IL-21 protein within the allergic asthmatic group, compared with the allergic control group. We also found increased IL21R transcripts and predicted IL-21 ligand activity in various disease-associated cell subsets.
CONCLUSIONS: IL-9 and IL-21 play important and non-redundant roles in allergic asthma by boosting ILC2s and TH2 cells, revealing a dual IL-9 and IL-21 targeting strategy as a new and testable approach.
OBJECTIVE: IL-9 and IL-21 boost the activation and proliferation of TH2 and ILC2s, but the relative importance and potential synergism between these γc cytokines is currently unknown.
METHODS: Using newly generated antibodies, we inhibited IL-9 and IL-21 alone or in combination, in various murine models of asthma. In a translational approach using segmental allergen challenge, we recently described elevated IL-9 levels in human allergic asthmatics in comparison to non-asthmatic controls. Here, we also measured IL-21 in both groups.
RESULTS: IL-9 played a central role in controlling innate IL-33 induced lung inflammation by promoting proliferation and activation of ILC2s, in an IL-21 independent manner. Conversely, chronic house dust mite induced airway inflammation, mainly driven by adaptive immunity, was solely dependent on IL-21, that controlled TH2 activation, eosinophilia, total serum IgE and formation of tertiary lymphoid structures. In a model of innate on adaptive immunity driven by papain allergen, a clear synergy was found between both pathways, since combined anti-IL-9 or anti-IL-21 blockade was superior in reducing key asthma features. In human bronchoalveolar lavage (BAL) samples we measured elevated IL-21 protein within the allergic asthmatic group, compared with the allergic control group. We also found increased IL21R transcripts and predicted IL-21 ligand activity in various disease-associated cell subsets.
CONCLUSIONS: IL-9 and IL-21 play important and non-redundant roles in allergic asthma by boosting ILC2s and TH2 cells, revealing a dual IL-9 and IL-21 targeting strategy as a new and testable approach.
摘要：
背景：哮喘通常伴有由TH2淋巴细胞或2型先天淋巴细胞（ILC2s）产生的富含IL-4，IL-5和IL-13细胞因子的2型免疫。白细胞介素-2家族细胞因子在分化过程中发挥关键作用,固有淋巴细胞和适应性淋巴细胞的稳态和效应子功能。
目的：IL-9和IL-21促进TH2和ILC2s的激活和增殖，但是这些γc细胞因子之间的相对重要性和潜在的协同作用目前尚不清楚。
方法：使用新产生的抗体，我们单独或联合抑制IL-9和IL-21，在各种哮喘小鼠模型中。在使用分段过敏原攻击的翻译方法中，我们最近描述了与非哮喘对照相比，人类过敏性哮喘患者的IL-9水平升高。这里,我们还测量了两组的IL-21。
结果：IL-9通过促进ILC2s的增殖和激活，在控制固有IL-33诱导的肺部炎症中起重要作用，以IL-21独立的方式。相反，慢性屋尘螨引起的气道炎症，主要由适应性免疫驱动，完全依赖于控制TH2激活的IL-21，嗜酸性粒细胞增多,总血清IgE和三级淋巴结构的形成。在由木瓜蛋白酶过敏原驱动的先天适应性免疫模型中，在这两种途径之间发现了明显的协同作用，因为联合使用抗IL-9或抗IL-21阻断在减轻哮喘的关键特征方面具有优势。在人支气管肺泡灌洗（BAL）样品中，我们测量了过敏性哮喘组中IL-21蛋白升高，与过敏对照组相比。我们还发现在各种疾病相关细胞亚群中IL21R转录物和预测的IL-21配体活性增加。
结论：IL-9和IL-21通过促进ILC2s和TH2细胞在过敏性哮喘中发挥重要且非冗余的作用，揭示了IL-9和IL-21双重靶向策略作为一种新的可测试的方法。
目的：IL-9和IL-21促进TH2和ILC2s的激活和增殖，但是这些γc细胞因子之间的相对重要性和潜在的协同作用目前尚不清楚。
方法：使用新产生的抗体，我们单独或联合抑制IL-9和IL-21，在各种哮喘小鼠模型中。在使用分段过敏原攻击的翻译方法中，我们最近描述了与非哮喘对照相比，人类过敏性哮喘患者的IL-9水平升高。这里,我们还测量了两组的IL-21。
结果：IL-9通过促进ILC2s的增殖和激活，在控制固有IL-33诱导的肺部炎症中起重要作用，以IL-21独立的方式。相反，慢性屋尘螨引起的气道炎症，主要由适应性免疫驱动，完全依赖于控制TH2激活的IL-21，嗜酸性粒细胞增多,总血清IgE和三级淋巴结构的形成。在由木瓜蛋白酶过敏原驱动的先天适应性免疫模型中，在这两种途径之间发现了明显的协同作用，因为联合使用抗IL-9或抗IL-21阻断在减轻哮喘的关键特征方面具有优势。在人支气管肺泡灌洗（BAL）样品中，我们测量了过敏性哮喘组中IL-21蛋白升高，与过敏对照组相比。我们还发现在各种疾病相关细胞亚群中IL21R转录物和预测的IL-21配体活性增加。
结论：IL-9和IL-21通过促进ILC2s和TH2细胞在过敏性哮喘中发挥重要且非冗余的作用，揭示了IL-9和IL-21双重靶向策略作为一种新的可测试的方法。
