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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:145

Article

Branchett, William J.^1,2  Stolting, Helen^1,2  Oliver, Robert A.^1,2  Walker, Simone A.^1,2  Puttur, Franz^1,2  Gregory, Lisa G.^1,2  Gabrysova, Leona³  Wilson, Mark S.^4,5  O'Garra, Anne^1,3  Lloyd, Clare M.^1,2 

[1] Natl Heart & Lung Inst, London, England

[2] Imperial Coll London, Asthma UK Ctr Allerg Mech Asthma, London, England

[3] Immunoregulat & Infect Lab, London, England

[4] Francis Crick Inst, Allergy & Antihelminth Immun Lab, London, England

[5] Genentech Inc, San Francisco, CA USA

关键词: Severe asthma;    type 2-low asthma;    IL-10;    immune regulation;    T cell;    macrophage;    dendritic cell;    IFN-gamma;   

DOI  :  10.1016/j.jaci.2019.08.006

来源: Elsevier

【 摘 要 】

Background: Although originally defined as a type 2 (T2) immune-mediated condition, non-T2 cytokines, such as IFN-gamma and IL-17A, have been implicated in asthma pathogenesis, particularly in patients with severe disease. IL-10 regulates T-H 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 T-H 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 a (IL-10Ra) knockout mice by means of repeated intranasal administration of house dust mite (HDM). IL-10 and IFN-gamma 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-gamma and IL-17A response to HDM, reducing IL-13 levels and airway eosinophilia without affecting IgE levels or airway hyperresponsiveness. The increased IFN-gamma response could be recapitulated by IL-10R alpha deletion in CD11c(+) myeloid cells or local IL-10R alpha blockade. Disruption of the T cell-myeloid IL-10 axis resulted in increased pulmonary monocyte-derived dendritic cell numbers and increased IFN-gamma-dependent expression of CXCR3 ligands by airway macrophages, which is suggestive of a feedforward loop of TH1 cell recruitment. Augmented IFN-gamma responses in the HDM allergic airway disease model were accompanied by increased disruption of airway epithelium, which was reversed by therapeutic blockade of IFN-gamma. Conclusions: IL-10 from effector T cells signals to CD11c(+) myeloid cells to suppress an atypical and pathogenic IFN-gamma response to inhaled HDM.

【 授权许可】

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