International Centre for Genetic Engineering and Biotechnology (ICGEB) and Division of Immunology, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Science, University of Cape Town, Cape Town, South Africa.
International Centre for Genetic Engineering and Biotechnology (ICGEB) and Division of Immunology, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Science, University of Cape Town, Cape Town, South Africa.
J Allergy Clin Immunol. 2016 Jun;137(6):1852-1862.e9. doi: 10.1016/j.jaci.2015.10.036. Epub 2015 Dec 11.
TH2 cells and their cytokines are associated with allergic asthma in human subjects and with mouse models of allergic airway disease. IL-4 signaling through the IL-4 receptor α (IL-4Rα) chain on CD4(+) T cells leads to TH2 cell differentiation in vitro, implying that IL-4Rα-responsive CD4(+) T cells are critical for the induction of allergic asthma. However, mechanisms regulating acute and chronic allergen-specific TH2 responses in vivo remain incompletely understood.
This study defines the requirements for IL-4Rα-responsive CD4(+) T cells and the IL-4Rα ligands IL-4 and IL-13 in the development of allergen-specific TH2 responses during the onset and chronic phase of experimental allergic airway disease.
Development of acute and chronic ovalbumin (OVA)-induced allergic asthma was assessed weekly in CD4(+) T cell-specific IL-4Rα-deficient BALB/c mice (Lck(cre)IL-4Rα(-/lox)) and respective control mice in the presence or absence of IL-4 or IL-13.
During acute allergic airway disease, IL-4 deficiency did not prevent the onset of TH2 immune responses and OVA-induced airway hyperresponsiveness or goblet cell hyperplasia, irrespective of the presence or absence of IL-4Rα-responsive CD4(+) T cells. In contrast, deficiency of IL-13 prevented allergic asthma, irrespective of the presence or absence of IL-4Rα-responsive CD4(+) T cells. Importantly, chronic allergic inflammation and airway hyperresponsiveness were dependent on IL-4Rα-responsive CD4(+) T cells. Deficiency in IL-4Rα-responsive CD4(+) T cells resulted in increased numbers of IL-17-producing T cells and, consequently, increased airway neutrophilia.
IL-4-responsive T helper cells are dispensable for acute OVA-induced airway disease but crucial in maintaining chronic asthmatic pathology.
TH2 细胞及其细胞因子与人类过敏哮喘以及过敏性气道疾病的小鼠模型相关。白细胞介素 4（IL-4）通过 CD4+T 细胞上的 IL-4 受体α（IL-4Rα）链传递信号，导致 TH2 细胞在体外分化，这意味着 IL-4Rα 反应性 CD4+T 细胞对于诱导过敏哮喘至关重要。然而，体内调节急性和慢性过敏原特异性 TH2 反应的机制仍不完全清楚。
本研究定义了 IL-4Rα 反应性 CD4+T 细胞以及 IL-4 和 IL-13 这两种 IL-4Rα 配体在实验性过敏性气道疾病的发作和慢性阶段过敏原特异性 TH2 反应发展中的需求。
在存在或不存在 IL-4 或 IL-13 的情况下，每周评估 CD4+T 细胞特异性 IL-4Rα 缺陷 BALB/c 小鼠（Lck(cre)IL-4Rα(-/lox)）及其相应对照小鼠中急性和慢性卵清蛋白（OVA）诱导的过敏性哮喘的发展。
在急性过敏性气道疾病中，无论是否存在 IL-4Rα 反应性 CD4+T 细胞，IL-4 缺陷均不能阻止 TH2 免疫反应和 OVA 诱导的气道高反应性或杯状细胞增生的发生。相比之下，IL-13 缺陷无论是否存在 IL-4Rα 反应性 CD4+T 细胞均可预防哮喘。重要的是，慢性过敏性炎症和气道高反应性依赖于 IL-4Rα 反应性 CD4+T 细胞。IL-4Rα 反应性 CD4+T 细胞缺陷导致产生白细胞介素 17 的 T 细胞数量增加，进而导致气道中性粒细胞增多。
IL-4 反应性辅助性 T 细胞对于 OVA 诱导的急性气道疾病不是必需的，但对于维持慢性哮喘病理是至关重要的。
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