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

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Title: Th17 responses in chronic allergic airway inflammation abrogate regulatory T-cell-mediated tolerance and contribute to airway remodeling
Author(s): Zhao, J
Lloyd, CM
Noble, A
Item 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.
Publication Date: 15-Aug-2012
Date of Acceptance: 13-Jul-2012
URI: http://hdl.handle.net/10044/1/40184
DOI: http://dx.doi.org/10.1038/mi.2012.76
ISSN: 1935-3456
Publisher: Nature Publishing Group
Start Page: 335
End Page: 346
Journal / Book Title: Mucosal Immunology
Volume: 6
Issue: 2
Sponsor/Funder: Medical Research Council (MRC)
Funder's Grant Number: G1000758
Copyright Statement: © 2012 Society for Mucosal Immunology
Keywords: 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
Lung
Respiratory Mucosa
T-Lymphocyte Subsets
Th2 Cells
Animals
Mice, Knockout
Mice
Asthma
Inflammation
Tretinoin
Dexamethasone
DNA-Binding Proteins
Transcription Factors
Interleukin-10
Interleukin-17
Allergens
Cell Differentiation
Immune Tolerance
Phenotype
Permeability
T-Lymphocytes, Regulatory
Interferon-gamma
Airway Remodeling
Th17 Cells
Immunology
06 Biological Sciences
11 Medical And Health Sciences
Publication Status: Published
Appears in Collections:National Heart and Lung Institute
Department of Medicine
Faculty of Medicine



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