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@article{Branchett:2020:10.1016/j.jaci.2019.08.006,
author = {Branchett, W and Stoelting, H and Oliver, R and Walker, S and Puttur, F and Gregory, L and Gabrysova, L and Wilson, M and O'Garra, A and Lloyd, C},
doi = {10.1016/j.jaci.2019.08.006},
journal = {Journal of Allergy and Clinical Immunology},
pages = {666--678.e9},
title = {A T cell-myeloid IL-10 axis regulates pathogenic IFN-γ-dependent immunity in a mouse model of type 2-low asthma},
url = {http://dx.doi.org/10.1016/j.jaci.2019.08.006},
volume = {145},
year = {2020}
}

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TY  - JOUR
AB  - BackgroundAlthough 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.MethodsAllergic 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.ResultsRepeated 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.ConclusionsIL-10 from effector T cells signals to CD11c+ myeloid cells to suppress an atypical and pathogenic IFN-γ response to inhaled HDM.
AU  - Branchett,W
AU  - Stoelting,H
AU  - Oliver,R
AU  - Walker,S
AU  - Puttur,F
AU  - Gregory,L
AU  - Gabrysova,L
AU  - Wilson,M
AU  - O'Garra,A
AU  - Lloyd,C
DO  - 10.1016/j.jaci.2019.08.006
EP  - 678
PY  - 2020///
SN  - 0091-6749
SP  - 666
TI  - A T cell-myeloid IL-10 axis regulates pathogenic IFN-γ-dependent immunity in a mouse model of type 2-low asthma
T2  - Journal of Allergy and Clinical Immunology
UR  - http://dx.doi.org/10.1016/j.jaci.2019.08.006
UR  - https://www.sciencedirect.com/science/article/pii/S0091674919310796?via%3Dihub
UR  - http://hdl.handle.net/10044/1/72992
VL  - 145
ER  -

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