Th17 responses in chronic allergic airway inflammation abrogate regulatory T-cell-mediated tolerance and contribute to airway remodeling
File(s)
Accepted version
Author(s)
Zhao, J
Lloyd, CM
Noble, A
Type
Journal Article
Abstract
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-α 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-γ 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.
Date Issued
2012-08-15
Date Acceptance
2012-07-13
Citation
Mucosal Immunology, 2012, 6 (2), pp.335-346
ISSN
1935-3456
Publisher
Nature Publishing Group
Start Page
335
End Page
346
Journal / Book Title
Mucosal Immunology
Volume
6
Issue
2
Copyright Statement
© 2012 Society for Mucosal Immunology
Sponsor
Medical Research Council (MRC)
Grant Number
G1000758
Subjects
Science & Technology
Life Sciences & Biomedicine
Immunology
IMMUNOLOGY
SEVERE ASTHMA
SURFACE EXPRESSION
MOUSE MODELS
TGF-BETA
MICE
INTERLEUKIN-17
IL-17
HYPERREACTIVITY
CYTOKINES
DEVELOP
Airway Remodeling
Allergens
Animals
Asthma
Cell Differentiation
DNA-Binding Proteins
Dexamethasone
Immune Tolerance
Inflammation
Interferon-gamma
Interleukin-10
Interleukin-17
Lung
Mice
Mice, Knockout
Permeability
Phenotype
Respiratory Mucosa
T-Lymphocyte Subsets
T-Lymphocytes, Regulatory
Th17 Cells
Th2 Cells
Transcription Factors
Tretinoin
06 Biological Sciences
11 Medical And Health Sciences
Publication Status
Published