整合素CD103鉴定出一组抑制过敏性气道炎症的高IL-10产生的FoxP3+调节性T细胞群
2021/11/24
摘要
背景：尽管FoxP3+调节性T(Treg)细胞构成高度异质性的细胞亚群，并且根据疾病环境具有不同的调节潜力，但不同的亚群或表型仍不明确。这阻碍了过敏性和自身免疫性疾病免疫治疗的发展。
目的：本研究旨在阐明在肺组织中参与抑制Th2介导的过敏性炎症的不同FoxP3+Treg亚群的特征。
方法：采用基于卵蛋白致敏和激发的已建立的过敏性气道疾病小鼠模型，分析炎症诱导和缓解过程中的FoxP3+Treg，并确定区分其最具抑制性表型的标记。我们还研发了一种新的敲入小鼠模型 (Foxp3cre Cd103dtr)，能够特异性消融 CD103+ FoxP3+ Treg 以进行功能研究。
结果：在小鼠过敏性气道炎症消退过程中，超过50%的FoxP3+Treg细胞表达整合素CD103，标志着FoxP3+Treg细胞产生高IL-10，增加免疫调节分子，如KLRG1、ICOS和CD127等的表达，并增强抑制Th2 介导的炎症反应的能力。CD103+FoxP3+Tregs在Foxp3cre Cd103dtr小鼠体内的特异性缺失可导致严重的肺泡毛细血管损伤、嗜酸性肺炎，并显著缩短动物的寿命，因此CD103+FoxP3+Tregs对于控制过敏性炎症至关重要。相反，过继转移CD103+FoxP3+Tregs可以有效地治疗疾病，以IL-10依赖的方式减弱Th2反应和过敏性炎症。
结论：本研究确定了一种新的调节性T细胞群，由CD103的表达决定，程序性预防2型炎症，并保持呼吸道的稳态。这具有重要的治疗意义。
CD103 integrin identifies a high IL-10-producing FoxP3 + regulatory T-cell population suppressing allergic airway inflammation
Sofia Tagkareli, Maria Salagianni, Ioanna-Evdokia Galani, Maria Manioudaki, Eleftherios Pavlos, Kalliopi Thanopoulou, Evangelos Andreakos
Abstract
BACKGROUND:Although FoxP3+ regulatory T (Treg) cells constitute a highly heterogeneous population, with different regulatory potential depending on the disease context, distinct subsets or phenotypes remain poorly defined. This hampers the development of immunotherapy for allergic and autoimmune disorders.
OBJECTIVE:The present study aimed at characterizing distinct FoxP3+ Treg subpopulations involved in the suppression of Th2-mediated allergic inflammation in the lung.
METHODS: We used an established mouse model of allergic airway disease based on ovalbumin sensitization and challenge to analyze FoxP3+ Tregs during the induction and resolution of inflammation, and identify markers that distinguish their most suppressive phenotypes. We also developed a new knock-in mouse model (Foxp3cre Cd103dtr ) enabling the specific ablation of CD103+ FoxP3+ Tregs for functional studies.
RESULTS: We found that during resolution of allergic airway inflammation in mice >50% of FoxP3+ Treg cells expressed the integrin CD103 which marks FoxP3+ Treg cells of high IL-10 production, increased expression of immunoregulatory molecules such as KLRG1, ICOS and CD127, and enhanced suppressive capacity for Th2-mediated inflammatory responses. CD103+ FoxP3+ Tregs were essential for keeping allergic inflammation under control as their specific depletion in Foxp3cre Cd103dtr mice lead to severe alveocapillary damage, eosinophilic pneumonia, and markedly reduced lifespan of the animals. Conversely, adoptive transfer of CD103+ FoxP3+ Tregs effectively treated disease, attenuating Th2 responses and allergic inflammation in an IL-10-dependent manner.
CONCLUSIONS: Our study identifies a novel regulatory T-cell population, defined by CD103 expression, programmed to prevent exuberant type 2 inflammation and keep homeostasis in the respiratory tract under control. This has important therapeutic implications.
背景：尽管FoxP3+调节性T(Treg)细胞构成高度异质性的细胞亚群，并且根据疾病环境具有不同的调节潜力，但不同的亚群或表型仍不明确。这阻碍了过敏性和自身免疫性疾病免疫治疗的发展。
目的：本研究旨在阐明在肺组织中参与抑制Th2介导的过敏性炎症的不同FoxP3+Treg亚群的特征。
方法：采用基于卵蛋白致敏和激发的已建立的过敏性气道疾病小鼠模型，分析炎症诱导和缓解过程中的FoxP3+Treg，并确定区分其最具抑制性表型的标记。我们还研发了一种新的敲入小鼠模型 (Foxp3cre Cd103dtr)，能够特异性消融 CD103+ FoxP3+ Treg 以进行功能研究。
结果：在小鼠过敏性气道炎症消退过程中，超过50%的FoxP3+Treg细胞表达整合素CD103，标志着FoxP3+Treg细胞产生高IL-10，增加免疫调节分子，如KLRG1、ICOS和CD127等的表达，并增强抑制Th2 介导的炎症反应的能力。CD103+FoxP3+Tregs在Foxp3cre Cd103dtr小鼠体内的特异性缺失可导致严重的肺泡毛细血管损伤、嗜酸性肺炎，并显著缩短动物的寿命，因此CD103+FoxP3+Tregs对于控制过敏性炎症至关重要。相反，过继转移CD103+FoxP3+Tregs可以有效地治疗疾病，以IL-10依赖的方式减弱Th2反应和过敏性炎症。
结论：本研究确定了一种新的调节性T细胞群，由CD103的表达决定，程序性预防2型炎症，并保持呼吸道的稳态。这具有重要的治疗意义。
(中日友好医院呼吸与危重症医学科 王静茹 摘译 林江涛 审校)
(Allergy. 2021 Oct 17. doi: 10.1111/all.15144.)
(Allergy. 2021 Oct 17. doi: 10.1111/all.15144.)
CD103 integrin identifies a high IL-10-producing FoxP3 + regulatory T-cell population suppressing allergic airway inflammation
Sofia Tagkareli, Maria Salagianni, Ioanna-Evdokia Galani, Maria Manioudaki, Eleftherios Pavlos, Kalliopi Thanopoulou, Evangelos Andreakos
Abstract
BACKGROUND:Although FoxP3+ regulatory T (Treg) cells constitute a highly heterogeneous population, with different regulatory potential depending on the disease context, distinct subsets or phenotypes remain poorly defined. This hampers the development of immunotherapy for allergic and autoimmune disorders.
OBJECTIVE:The present study aimed at characterizing distinct FoxP3+ Treg subpopulations involved in the suppression of Th2-mediated allergic inflammation in the lung.
METHODS: We used an established mouse model of allergic airway disease based on ovalbumin sensitization and challenge to analyze FoxP3+ Tregs during the induction and resolution of inflammation, and identify markers that distinguish their most suppressive phenotypes. We also developed a new knock-in mouse model (Foxp3cre Cd103dtr ) enabling the specific ablation of CD103+ FoxP3+ Tregs for functional studies.
RESULTS: We found that during resolution of allergic airway inflammation in mice >50% of FoxP3+ Treg cells expressed the integrin CD103 which marks FoxP3+ Treg cells of high IL-10 production, increased expression of immunoregulatory molecules such as KLRG1, ICOS and CD127, and enhanced suppressive capacity for Th2-mediated inflammatory responses. CD103+ FoxP3+ Tregs were essential for keeping allergic inflammation under control as their specific depletion in Foxp3cre Cd103dtr mice lead to severe alveocapillary damage, eosinophilic pneumonia, and markedly reduced lifespan of the animals. Conversely, adoptive transfer of CD103+ FoxP3+ Tregs effectively treated disease, attenuating Th2 responses and allergic inflammation in an IL-10-dependent manner.
CONCLUSIONS: Our study identifies a novel regulatory T-cell population, defined by CD103 expression, programmed to prevent exuberant type 2 inflammation and keep homeostasis in the respiratory tract under control. This has important therapeutic implications.
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