A T cell-myeloid IL-10 axis regulates pathogenic IFN-γ-dependent immunity in a mouse model of type 2-low asthma

Autor: Branchett, William J., Stölting, Helen, Oliver, Robert A., Walker, Simone A., Puttur, Franz, Gregory, Lisa G., Gabryšová, Leona, Wilson, Mark S., O'Garra, Anne, Lloyd, Clare M.
Rok vydání: 2019
Předmět:
Severe asthma
BAL
Bronchoalveolar lavage
dendritic cell
AHR
Airway hyperresponsiveness
APC
Antigen-presenting cell
FoxP3
Forkhead box P3
macrophage
PAS
Periodic acid–Schiff
type 2–low asthma
Article
Teff
Effector T
Interferon-gamma
Mice
AM
Airway macrophage
Hypersensitivity
T1
Type 1
Animals
PMA
Phorbol 12-myristate 13-acetate
Myeloid Cells
HDM
House dust mite
IFN-γ
cRPMI
Complete RPMI
Mice
Knockout
moDC
Monocyte-derived dendritic cell
cDC2
Type 2 conventional dendritic cell
T2
Type 2
immune regulation
Pyroglyphidae
T cell
mLN
Mediastinal lymph node
T-Lymphocytes
Helper-Inducer
Allergens
Treg
Regulatory T
DC
Dendritic cell
IL-10Rα
IL-10 receptor α
Asthma
Interleukin-10
Mice
Inbred C57BL
Disease Models
Animal
AAD
Allergic airway disease
IMM
Inflammatory monocyte and macrophage
IL-10
IM
Interstitial macrophage
T17
Type 17
Ct
Threshold cycle
Female
Bronchial Hyperreactivity
Zdroj: The Journal of Allergy and Clinical Immunology
ISSN: 1097-6825
Popis: Background Although originally defined as a type 2 (T2) immune-mediated condition, non-T2 cytokines, such as IFN-γ and IL-17A, have been implicated in asthma pathogenesis, particularly in patients with severe disease. IL-10 regulates TH cell phenotypes and can dampen T2 immunity to allergens, but its functions in controlling non-T2 cytokine responses in asthmatic patients are unclear. Objective We sought to determine how IL-10 regulates the balance of TH cell responses to inhaled allergen. Methods Allergic airway disease was induced in wild-type, IL-10 reporter, and conditional IL-10 or IL-10 receptor α (IL-10Rα) knockout mice by means of repeated intranasal administration of house dust mite (HDM). IL-10 and IFN-γ signaling were disrupted by using blocking antibodies. Results Repeated HDM inhalation induced a mixed IL-13/IL-17A response and accumulation of IL-10–producing forkhead box P3–negative effector CD4+ T cells in the lungs. Ablation of T cell–derived IL-10 increased the IFN-γ and IL-17A response to HDM, reducing IL-13 levels and airway eosinophilia without affecting IgE levels or airway hyperresponsiveness. The increased IFN-γ response could be recapitulated by IL-10Rα deletion in CD11c+ myeloid cells or local IL-10Rα blockade. Disruption of the T cell–myeloid IL-10 axis resulted in increased pulmonary monocyte–derived dendritic cell numbers and increased IFN-γ–dependent expression of CXCR3 ligands by airway macrophages, which is suggestive of a feedforward loop of TH1 cell recruitment. Augmented IFN-γ responses in the HDM allergic airway disease model were accompanied by increased disruption of airway epithelium, which was reversed by therapeutic blockade of IFN-γ. Conclusions IL-10 from effector T cells signals to CD11c+ myeloid cells to suppress an atypical and pathogenic IFN-γ response to inhaled HDM.
Graphical abstract
Databáze: OpenAIRE
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