趋化因子CCL19促进2型T细胞分化和过敏性气道炎症
2023/11/23
摘要
背景：过敏性哮喘主要由过敏原特异性2型辅助性T（Th2）细胞驱动，初始CD4+T细胞与从肺部迁移的携带过敏原的树突状细胞（DC）相互作用后Th2细胞得以在区域淋巴结中发育。上述迁移事件依赖于CCR7及其趋化因子配体CCL21。然而，目前尚不清楚另一种CCR7配体CCL19是否在过敏性气道疾病中发挥作用。
目的：本研究旨在确定CCL19在Th2分化和过敏性气道疾病中的作用。
方法：采用CCL19缺陷小鼠构建过敏性哮喘动物模型。将来自野生型（WT）和CCL19缺陷小鼠的DC或成纤维网状细胞（FRCs）与初始CD4+T细胞培养，采用ELISA法测定细胞因子水平。将重组CCL19加入CD4+T细胞培养物中，采用RNA测序和qPCR测定基因表达。采用流式细胞术评估转录因子的激活情况。
结果：与无CCL19缺陷的小鼠肺组织相比，CCL19缺陷小鼠的肺组织中过敏性气道炎症减轻，气道高反应性改善，且IL-4和IL-13产生减少。与CCL19缺陷的DC或FRCs共培养的初始CD4+T细胞产生的2型细胞因子量低于与野生型细胞共培养的T细胞。重组CCL19可增加STAT5的磷酸化，并诱导Th2和IL-2信号通路相关的基因表达。
结论：本研究结果创新性地揭示了CCL19可在过敏性气道疾病中诱导Th2细胞，并表明阻断该途径可能有助于降低过敏性哮喘的发病率或严重程度。
Chemokine CCL19 promotes type 2 T cell differentiation and allergic airway inflammation.
Nakano K, Whitehead GS, Lyons-Cohen MR, Grimm SA, Wilkinson CL, Izumi G, Livraghi-Butrico A, Cook DN, Nakano H.
Abstract
BACKGROUND:Allergic asthma is driven largely by allergen-specific type 2 T helper (Th2) cells, which develop in regional lymph nodes upon the interaction of naïve CD4+ T cells with allergen-bearing dendritic cells (DCs) that migrate from the lung. This migration event is dependent on CCR7 and its chemokine ligand, CCL21. However, is has been unclear whether the other CCR7 ligand, CCL19, has a role in allergic airway disease.
OBJECTIVE:We sought to define the role of CCL19 in Th2 differentiation and allergic airway disease.
METHODS:CCL19-deficient mice were studied in an animal model of allergic asthma. DCs or fibroblastic reticular cells (FRCs) from wildtype (WT) and CCL19-deficient mice were cultured with naïve CD4+ T cells, and cytokine production was measured by ELISA. Recombinant CCL19 was added to CD4+ T cell cultures, and gene expression was assessed by RNA-sequencing and qPCR. Transcription factor activation was assessed by flow cytometry.
RESULTS:Lungs of CCL19-deficient mice had less allergic airway inflammation, reduced airway hyperresponsiveness, and less IL-4 and IL-13 production compared with lungs of CCL19-sufficient animals. Naïve CD4+ T cells co-cultured with CCL19-deficient DCs or FRCs produced lower amounts of type 2 cytokines than did T cells co-cultured with their WT counterparts. Recombinant CCL19 increased phosphorylation of STAT5 and induced expression of genes associated with Th2 and IL-2 signaling pathways.
CONCLUSION:Our results reveal a novel, Th2-inducing function of CCL19 in allergic airway disease and suggest that strategies to block this pathway might help to reduce the incidence or severity of allergic asthma.
背景：过敏性哮喘主要由过敏原特异性2型辅助性T（Th2）细胞驱动，初始CD4+T细胞与从肺部迁移的携带过敏原的树突状细胞（DC）相互作用后Th2细胞得以在区域淋巴结中发育。上述迁移事件依赖于CCR7及其趋化因子配体CCL21。然而，目前尚不清楚另一种CCR7配体CCL19是否在过敏性气道疾病中发挥作用。
目的：本研究旨在确定CCL19在Th2分化和过敏性气道疾病中的作用。
方法：采用CCL19缺陷小鼠构建过敏性哮喘动物模型。将来自野生型（WT）和CCL19缺陷小鼠的DC或成纤维网状细胞（FRCs）与初始CD4+T细胞培养，采用ELISA法测定细胞因子水平。将重组CCL19加入CD4+T细胞培养物中，采用RNA测序和qPCR测定基因表达。采用流式细胞术评估转录因子的激活情况。
结果：与无CCL19缺陷的小鼠肺组织相比，CCL19缺陷小鼠的肺组织中过敏性气道炎症减轻，气道高反应性改善，且IL-4和IL-13产生减少。与CCL19缺陷的DC或FRCs共培养的初始CD4+T细胞产生的2型细胞因子量低于与野生型细胞共培养的T细胞。重组CCL19可增加STAT5的磷酸化，并诱导Th2和IL-2信号通路相关的基因表达。
结论：本研究结果创新性地揭示了CCL19可在过敏性气道疾病中诱导Th2细胞，并表明阻断该途径可能有助于降低过敏性哮喘的发病率或严重程度。
(中日友好医院呼吸与危重症医学科 张婧媛 摘译 林江涛 审校)
(J Allergy Clin Immunol. 2023 Nov 11:S0091-6749(23)01398-2. doi: 10.1016/j.jaci.2023.10.024.)
(J Allergy Clin Immunol. 2023 Nov 11:S0091-6749(23)01398-2. doi: 10.1016/j.jaci.2023.10.024.)
Chemokine CCL19 promotes type 2 T cell differentiation and allergic airway inflammation.
Nakano K, Whitehead GS, Lyons-Cohen MR, Grimm SA, Wilkinson CL, Izumi G, Livraghi-Butrico A, Cook DN, Nakano H.
Abstract
BACKGROUND:Allergic asthma is driven largely by allergen-specific type 2 T helper (Th2) cells, which develop in regional lymph nodes upon the interaction of naïve CD4+ T cells with allergen-bearing dendritic cells (DCs) that migrate from the lung. This migration event is dependent on CCR7 and its chemokine ligand, CCL21. However, is has been unclear whether the other CCR7 ligand, CCL19, has a role in allergic airway disease.
OBJECTIVE:We sought to define the role of CCL19 in Th2 differentiation and allergic airway disease.
METHODS:CCL19-deficient mice were studied in an animal model of allergic asthma. DCs or fibroblastic reticular cells (FRCs) from wildtype (WT) and CCL19-deficient mice were cultured with naïve CD4+ T cells, and cytokine production was measured by ELISA. Recombinant CCL19 was added to CD4+ T cell cultures, and gene expression was assessed by RNA-sequencing and qPCR. Transcription factor activation was assessed by flow cytometry.
RESULTS:Lungs of CCL19-deficient mice had less allergic airway inflammation, reduced airway hyperresponsiveness, and less IL-4 and IL-13 production compared with lungs of CCL19-sufficient animals. Naïve CD4+ T cells co-cultured with CCL19-deficient DCs or FRCs produced lower amounts of type 2 cytokines than did T cells co-cultured with their WT counterparts. Recombinant CCL19 increased phosphorylation of STAT5 and induced expression of genes associated with Th2 and IL-2 signaling pathways.
CONCLUSION:Our results reveal a novel, Th2-inducing function of CCL19 in allergic airway disease and suggest that strategies to block this pathway might help to reduce the incidence or severity of allergic asthma.
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