Inflammation, Repair and Development, National Heart and Lung Institute, Imperial College London, London, UK.
Respiratory Paediatrics, Royal Brompton Hospital and National Heart and Lung Institute, Imperial College London, London, UK.
Sci Immunol. 2018 Sep 7;3(27). doi: 10.1126/sciimmunol.aan4128.
Airway hyperresponsiveness (AHR) is a critical feature of wheezing and asthma in children, but the initiating immune mechanisms remain unconfirmed. We demonstrate that both recombinant interleukin-33 (rIL-33) and allergen [house dust mite (HDM) or ] exposure from day 3 of life resulted in significantly increased pulmonary IL-13CD4 T cells, which were indispensable for the development of AHR. In contrast, adult mice had a predominance of pulmonary LinCD45CD90IL-13 type 2 innate lymphoid cells (ILC2s) after administration of rIL-33. HDM exposure of neonatal IL-33 knockout (KO) mice still resulted in AHR. However, neonatal CD4IL-13 KO mice (lacking IL-13CD4 T cells) exposed to allergen from day 3 of life were protected from AHR despite persistent pulmonary eosinophilia, elevated IL-33 levels, and IL-13 ILCs. Moreover, neonatal mice were protected from AHR when inhaled (an environmental bacterial isolate found in cattle farms, which is known to protect from childhood asthma) was administered concurrent with HDM. blocked the expansion of pulmonary IL-13CD4 T cells, whereas IL-13 ILCs and IL-33 remained elevated. Administration of mirrored the findings from the CD4IL-13 KO mice, providing a translational approach for disease protection in early life. These data demonstrate that IL-13CD4 T cells, rather than IL-13 ILCs or IL-33, are critical for inception of allergic AHR in early life.
气道高反应性（AHR）是儿童喘息和哮喘的一个关键特征，但引发免疫机制仍未得到证实。我们证明，重组白细胞介素 33（rIL-33）和过敏原[屋尘螨（HDM）或]暴露从生命的第 3 天开始，导致肺中 IL-13CD4 T 细胞显著增加，这对于 AHR 的发展是必不可少的。相比之下，成年小鼠在给予 rIL-33 后，肺中的 LinCD45CD90IL-13 型 2 先天淋巴样细胞（ILC2）占优势。然而，新生 IL-33 敲除（KO）小鼠暴露于 HDM 仍然导致 AHR。然而，新生 CD4IL-13 KO 小鼠（缺乏 IL-13CD4 T 细胞）从生命的第 3 天开始接触过敏原，尽管持续存在肺嗜酸性粒细胞增多、IL-33 水平升高和 IL-13 ILC，但仍能免受 AHR 影响。此外，当新生小鼠同时给予（一种在奶牛场发现的环境细菌分离株，已知可预防儿童哮喘）时，可免受 AHR 影响。阻断了肺中 IL-13CD4 T 细胞的扩张，而 IL-13 ILC 和 IL-33 仍然升高。给予与 CD4IL-13 KO 小鼠的研究结果相似，为早期生命中的疾病保护提供了一种转化方法。这些数据表明，IL-13CD4 T 细胞而不是 IL-13 ILC 或 IL-33，对于早期生命中过敏性 AHR 的发生是至关重要的。
