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

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 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.

We sought to determine how IL-10 regulates the balance of T_H cell responses to inhaled allergen.

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.

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 T_H1 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.

IL-10 from effector T cells signals to CD11c⁺ myeloid cells to suppress an atypical and pathogenic IFN-γ response to inhaled HDM.