在TH2型低哮喘小鼠模型中，T细胞骨髓IL-10轴调节致病性IFN-γ依赖性免疫
2020/02/11
摘要
背景：尽管最初定义为2型 (T2)免疫介导的病症,非T2细胞因子,如IFN-γ和IL-17A,一直参与哮喘发病机制,尤其是严重的疾病。IL-10调节协助型T细胞(Th)表型，抑制T2对过敏原的免疫，但其在控制哮喘非T2细胞因子反应中的作用尚不清楚。目的:确定IL-10如何调节Th细胞对吸入过敏原的平衡。
方法：过敏性呼吸道疾病(AAD) 通过反复对屋内尘螨(HDM)的鼻内管理，在野生型,IL-10信使和条件性IL-10或IL-10受体α(IL-10Rα)基因敲除小鼠中被诱导。利用阻遏抗体IL - 10和IFN-γ传递信息被中断。
结果：反复吸入HDM诱导肺内混合的IL-13/IL-17A反应和IL -10产生的FoxP3-效应剂CD4+ T细胞的积累。消除T细胞起源的IL - 10增加IFN-γ和IL-17A对HDM反应,减少IL-13水平和气道嗜酸细胞，而不影响IgE水平和或气道高反应性。增加IFN-γ反应可以被总结为CD11c +髓细胞中IL-10Rα删除或局部IL-10Rα阻滞。T cell-髓样IL- 10轴中断导致肺单核粒细胞性树突状细胞数量增加和通过气道巨噬细胞，IFN-γ依赖性气道CXCR3配体的表达的增加,暗示一个Th1细胞募集的正反馈循环回路。在HDM AAD模型中增强IFN-γ的反应都伴随着增加气道上皮细胞的破坏,这逆转了IFN-γ治疗性阻滞的方法。
结论：IL - 10的效应T细胞发射信号给CD11c +髓细胞来抑制非典型和致病性对吸入HDM的 IFN-γ反应。
A T cell-myeloid IL-10 axis regulates pathogenic IFN-γ-dependent immunity in a mouse model of type 2-low asthma
William J. Branchett ,et al,JACI, August 22, 2019
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.
背景：尽管最初定义为2型 (T2)免疫介导的病症,非T2细胞因子,如IFN-γ和IL-17A,一直参与哮喘发病机制,尤其是严重的疾病。IL-10调节协助型T细胞(Th)表型，抑制T2对过敏原的免疫，但其在控制哮喘非T2细胞因子反应中的作用尚不清楚。目的:确定IL-10如何调节Th细胞对吸入过敏原的平衡。
方法：过敏性呼吸道疾病(AAD) 通过反复对屋内尘螨(HDM)的鼻内管理，在野生型,IL-10信使和条件性IL-10或IL-10受体α(IL-10Rα)基因敲除小鼠中被诱导。利用阻遏抗体IL - 10和IFN-γ传递信息被中断。
结果：反复吸入HDM诱导肺内混合的IL-13/IL-17A反应和IL -10产生的FoxP3-效应剂CD4+ T细胞的积累。消除T细胞起源的IL - 10增加IFN-γ和IL-17A对HDM反应,减少IL-13水平和气道嗜酸细胞，而不影响IgE水平和或气道高反应性。增加IFN-γ反应可以被总结为CD11c +髓细胞中IL-10Rα删除或局部IL-10Rα阻滞。T cell-髓样IL- 10轴中断导致肺单核粒细胞性树突状细胞数量增加和通过气道巨噬细胞，IFN-γ依赖性气道CXCR3配体的表达的增加,暗示一个Th1细胞募集的正反馈循环回路。在HDM AAD模型中增强IFN-γ的反应都伴随着增加气道上皮细胞的破坏,这逆转了IFN-γ治疗性阻滞的方法。
结论：IL - 10的效应T细胞发射信号给CD11c +髓细胞来抑制非典型和致病性对吸入HDM的 IFN-γ反应。
（中国医科大学附属第一医院 李文扬 摘译 杨冬 审校）
（William J. Branchett ,et al,JACI, August 22, 2019）
（William J. Branchett ,et al,JACI, August 22, 2019）
A T cell-myeloid IL-10 axis regulates pathogenic IFN-γ-dependent immunity in a mouse model of type 2-low asthma
William J. Branchett ,et al,JACI, August 22, 2019
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.
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集落刺激因子1及其受体是过敏性哮喘的新的潜在治疗靶点
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哮喘中的嗜酸性粒细胞炎症及有缺陷的上皮细胞的翻译控制
