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

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Title: A T cell-myeloid IL-10 axis regulates pathogenic IFN-γ-dependent immunity in a mouse model of type 2-low asthma
Authors: Branchett, W
Stoelting, H
Oliver, R
Walker, S
Puttur, F
Gregory, L
Gabrysova, L
Wilson, M
O'Garra, A
Lloyd, C
Item Type: Journal Article
Abstract: 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 severe disease. IL-10 regulates T helper (Th) cell phenotypes and can dampen T2 immunity to allergens, but its functions in controlling non-T2 cytokine responses in asthma are unclear. Objective: Determine how IL-10 regulates the balance of Th cell responses to inhaled allergen. Methods Allergic airway disease (AAD) was induced in wild-type, IL-10 reporter and conditional IL-10 or IL-10 receptor α (IL-10Rα) knockout mice, by repeated intranasal administration of house dust mite (HDM). IL-10 and IFN-γ signalling were disrupted using blocking antibodies. Results Repeated HDM inhalation induced a mixed IL-13/IL-17A response and accumulation of IL-10-producing FoxP3- 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 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 elevated pulmonary monocyte-derived dendritic cell numbers and increased IFN-γ-dependent expression of CXCR3 ligands by airway macrophages, suggestive of a feedforward loop of Th1 cell recruitment. Augmented IFN-γ responses in the HDM AAD 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.
Issue Date: Feb-2020
Date of Acceptance: 7-Aug-2019
URI: http://hdl.handle.net/10044/1/72992
DOI: 10.1016/j.jaci.2019.08.006
ISSN: 0091-6749
Publisher: Elsevier
Start Page: 666
End Page: 678.e9
Journal / Book Title: Journal of Allergy and Clinical Immunology
Volume: 145
Issue: 2
Copyright Statement: © 2019 The Authors. Published by Elsevier Inc. on behalf of the American Academy ofAllergy, Asthma & Immunology. This is an open access article under the CC BY li-cense (http://creativecommons.org/licenses/by/4.0/).
Sponsor/Funder: Wellcome Trust
Funder's Grant Number: 107059/Z/15/Z
Keywords: IFN-γ
Severe asthma
T cell
dendritic cell
immune regulation
type 2–low asthma
1107 Immunology
Publication Status: Published
Online Publication Date: 2019-08-22
Appears in Collections:National Heart and Lung Institute