Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
J Allergy Clin Immunol. 2013 Jun;131(6):1644-52. doi: 10.1016/j.jaci.2013.03.002. Epub 2013 Apr 28.
Induction of endogenous regulatory T (Treg) cells represents an exciting new potential modality for treating allergic diseases, such as asthma. Treg cells have been implicated in the regulation of asthma, but the anatomic location in which they exert their regulatory function and the mechanisms controlling the migration necessary for their suppressive function in asthma are not known. Understanding these aspects of Treg cell biology will be important for harnessing their power in the clinic.
We sought to determine the anatomic location at which Treg cells exert their regulatory function in the sensitization and effector phases of allergic asthma and to determine the chemokine receptors that control the migration of Treg cells to these sites in vivo in both mice and human subjects.
The clinical efficacy and anatomic location of adoptively transferred chemokine receptor-deficient CD4(+)CD25(+) forkhead box protein 3-positive Treg cells was determined in the sensitization and effector phases of allergic airway inflammation in mice. The chemokine receptor expression profile was determined on Treg cells recruited into the human airway after bronchoscopic segmental allergen challenge of asthmatic patients.
We show that CCR7, but not CCR4, is required on Treg cells to suppress allergic airway inflammation during the sensitization phase. In contrast, CCR4, but not CCR7, is required on Treg cells to suppress allergic airway inflammation during the effector phase. Consistent with our murine studies, human subjects with allergic asthma had an increase in CCR4-expressing functional Treg cells in the lungs after segmental allergen challenge.
The location of Treg cell function differs during allergic sensitization and allergen-induced recall responses in the lung, and this differential localization is critically dependent on differential chemokine function.
诱导内源性调节性 T（Treg）细胞代表了一种治疗过敏性疾病（如哮喘）的新的潜在治疗方法。Treg 细胞已被认为与哮喘的调节有关，但它们发挥调节功能的解剖位置以及控制其在哮喘中发挥抑制功能所需的迁移机制尚不清楚。了解 Treg 细胞生物学的这些方面对于在临床上利用它们的力量将是重要的。
我们试图确定 Treg 细胞在过敏性哮喘的致敏和效应阶段发挥其调节功能的解剖位置，并确定控制 Treg 细胞向这些部位在体内迁移的趋化因子受体，包括在小鼠和人类受试者中。
在小鼠过敏性气道炎症的致敏和效应阶段，确定过继转移趋化因子受体缺陷型 CD4(+)CD25(+)叉头框蛋白 3 阳性 Treg 细胞的临床疗效和解剖位置。在支气管镜分段过敏原挑战哮喘患者后，确定募集到人类气道中的 Treg 细胞的趋化因子受体表达谱。
我们表明，在致敏阶段，CCR7 而不是 CCR4，是 Treg 细胞抑制过敏性气道炎症所必需的。相比之下，在效应阶段，CCR4 而不是 CCR7，是 Treg 细胞抑制过敏性气道炎症所必需的。与我们的小鼠研究一致，哮喘患者在分段过敏原挑战后，肺部表达 CCR4 的功能性 Treg 细胞增加。
Treg 细胞功能在肺部过敏致敏和过敏原诱导的回忆反应中的位置不同，这种差异定位取决于趋化因子功能的差异。
