IL-2 family cytokines IL-9 and IL-21 differentially regulate innate and adaptive type 2 immunity in asthma

IF 11.4 1区医学 Q1 ALLERGY

Journal of Allergy and Clinical Immunology Pub Date : 2024-11-01 DOI:10.1016/j.jaci.2024.07.024

Fabian Bick MSc , Claudia M. Brenis Gómez MD , Inés Lammens MD , Justine Van Moorleghem BSc , Caroline De Wolf BSc , Sam Dupont BSc , Laure Dumoutier PhD , Neal P. Smith MSc , Alexandra-Chloé Villani PhD , Robin Browaeys PhD , Jehan Alladina MD , Alexis M. Haring BSc , Benjamin D. Medoff MD , Josalyn L. Cho MD , René Bigirimana PhD , Joao Vieira MSc , Hamida Hammad PhD , Christophe Blanchetot PhD , Martijn J. Schuijs PhD , Bart N. Lambrecht MD, PhD

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引用次数: 0

Abstract

Background

Asthma is often accompanied by type 2 immunity rich in IL-4, IL-5, and IL-13 cytokines produced by T_H2 lymphocytes or type 2 innate lymphoid cells (ILC2s). IL-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 activation and proliferation of T_H2 and ILC2s, but the relative importance and potential synergism between these γ common chain cytokines are 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 subjects with allergic asthma compared with nonasthmatic 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, which controlled T_H2 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, as combined anti-IL-9 or anti-IL-21 blockade was superior in reducing key asthma features. In human bronchoalveolar lavage 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 nonredundant roles in allergic asthma by boosting ILC2s and T_H2 cells, revealing a dual IL-9 and IL-21 targeting strategy as a new and testable approach.

Abstract Image

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白细胞介素-2 家族细胞因子 IL-9 和 IL-21 对哮喘的先天性和适应性 2 型免疫有不同的调节作用。

背景：哮喘通常伴随着由TH2淋巴细胞或2型先天性淋巴细胞（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 家族细胞因子在先天性和适应性淋巴细胞的分化、平衡和效应功能中发挥着关键作用：目的：IL-9 和 IL-21 可促进 TH2 和 ILC2 的活化和增殖，但这些 γc 细胞因子之间的相对重要性和潜在协同作用目前尚不清楚：我们使用新生成的抗体，在各种哮喘小鼠模型中单独或联合抑制了 IL-9 和 IL-21。最近，我们利用分段过敏原挑战的转化方法，描述了与非哮喘对照组相比，人类过敏性哮喘患者体内 IL-9 水平的升高。在这里，我们还测量了两组患者的 IL-21 水平：结果：IL-9通过促进ILC2的增殖和活化，在控制先天性IL-33诱导的肺部炎症中发挥了核心作用，其方式与IL-21无关。相反，主要由适应性免疫驱动的慢性屋尘螨诱导的气道炎症则完全依赖于 IL-21，它控制着 TH2 的活化、嗜酸性粒细胞增多、血清 IgE 总量和三级淋巴结构的形成。在一个由木瓜蛋白酶过敏原驱动的先天性和适应性免疫模型中，发现这两种途径之间有明显的协同作用，因为联合阻断抗IL-9或抗IL-21能更好地减少哮喘的主要特征。在人体支气管肺泡灌洗液（BAL）样本中，我们测得过敏性哮喘组的 IL-21 蛋白高于过敏性对照组。我们还在各种疾病相关细胞亚群中发现了 IL21R 转录物的增加和 IL-21 配体活性的预测：IL-9和IL-21通过增强ILC2和TH2细胞在过敏性哮喘中发挥着重要而非多余的作用，揭示了IL-9和IL-21双重靶向策略是一种新的可测试方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Allergy and Clinical Immunology 医学-过敏

CiteScore

25.90

自引率

7.70%

发文量

1302

审稿时长

38 days

期刊介绍： The Journal of Allergy and Clinical Immunology is a prestigious publication that features groundbreaking research in the fields of Allergy, Asthma, and Immunology. This influential journal publishes high-impact research papers that explore various topics, including asthma, food allergy, allergic rhinitis, atopic dermatitis, primary immune deficiencies, occupational and environmental allergy, and other allergic and immunologic diseases. The articles not only report on clinical trials and mechanistic studies but also provide insights into novel therapies, underlying mechanisms, and important discoveries that contribute to our understanding of these diseases. By sharing this valuable information, the journal aims to enhance the diagnosis and management of patients in the future.