Th17 responses in chronic allergic airway inflammation abrogate regulatory T-cell-mediated tolerance and contribute to airway remodeling

被引:190
作者
Zhao, J. [1 ,2 ]
Lloyd, C. M. [3 ,4 ]
Noble, A. [1 ,2 ]
机构
[1] Kings Coll London, MRC, Dept Asthma Allergy & Resp Sci, London WC2R 2LS, England
[2] Kings Coll London, Asthma UK Ctr Allerg Mech Asthma, London WC2R 2LS, England
[3] Univ London Imperial Coll Sci Technol & Med, MRC, London, England
[4] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Asthma UK Ctr Allerg Mech Asthma, London, England
关键词
SEVERE ASTHMA; SURFACE EXPRESSION; MOUSE MODELS; TGF-BETA; INTERLEUKIN-17; IL-17; DEVELOP; SUPPRESSION; INDUCTION; RESISTANT;
D O I
10.1038/mi.2012.76
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
The role of T-helper type 17 (Th17) responses in airway remodeling in asthma is currently unknown. We demonstrate that both parenteral and mucosal allergen sensitization, followed by allergen inhalation, leads to Th17-biased lung immune responses. Unlike Th17 cells generated in vitro, lung Th17 cells did not produce tumor necrosis factor-alpha or interleukin (IL)-22. Eosinophilia predominated in acute inflammation, while neutrophilia and IL-17 increased in chronic disease. Allergen-induced tolerance involved Foxp3-, Helios-, and glycoprotein-A repetitions predominant-expressing regulatory T cells (Treg) and IL-10/interferon-gamma priming. This Treg phenotype was altered in inflamed lungs and abrogated by inhalation of IL-17. Using Th17-deficient mice with genetic disruption of gp130 in T cells, we showed that Th17 cells induce airway remodeling independent of the Th2 response. All-trans retinoic acid administration ameliorated Th17-mediated disease and increased Treg activity, while dexamethasone inhibited eosinophilia but not neutrophilia, and enhanced Th17 development in vitro. Targeting the Th17/Treg axis might therefore be therapeutic in neutrophilic and glucocorticoid-refractory asthma.
引用
收藏
页码:335 / 346
页数:12
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