A switch in regulatory T cells through farm exposure during immune maturation in childhood
A switch in regulatory T cells through farm exposure during immune maturation in childhood
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DOI：
10.1111/all.13069
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发表时间：
2017-04-01
期刊：
影响因子：
12.4
通讯作者：
Schaub, B.
中科院分区：
文献类型：
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作者：
Schroeder, P. C.;Illi, S.;Schaub, B.
背景农场暴露可以防止生命早期发生过敏。 4.5 岁时，通过接触农场牛奶来预防哮喘的作用部分是由调节性 T 细胞 (Treg) 介导的。本研究的目的是调查儿童免疫成熟期间通过 Tregs 发挥哮喘保护农场效应的关键时间窗口。方法对来自 PASTURE/EFRAIM 出生队列（流式细胞术）的 111 名儿童（56 名农场儿童和 55 名参照儿童）在 4.5 岁和 6 岁时对 Tregs 进行纵向评估。外周血单核细胞采用佛波醇 12-肉豆蔻酸酯 13-乙酸酯/离子霉素 (PI) 或脂多糖 (LPS) 进行未刺激 (U) 培养，并进行 Tregs 染色 (CD4(+)CD25(high)FOXP3(upper20%)）。离体测量 Treg/Th1/Th2/Th17 相关细胞标志物的 mRNA 表达。评估了 Tregs 对效应细胞和细胞因子的抑制能力。父母回答了评估从出生到6岁农场暴露和临床表型的详细调查问卷。结果刺激前后Treg百分比和离体FOXP3mRNA表达从4.5岁到6岁下降（P(U,LPS) < 0.001; P(PI) = 0.051; P(FOXP3) < 0.001）。高与低农场牛奶和动物稳定暴露与 6 岁时 LPS 刺激的 Treg 百分比下降相关 (P(LPS) = 0.045）。 6 岁时 LPS 刺激的 Treg 百分比升高与哮喘风险增加相关（aOR = 11.29，CI：0.96-132.28，P = 0.053）。与非哮喘患者相比，哮喘患者的 Tregs 抑制 IFN-（P = 0.015）和 IL-9（P = 0.023）的效率较低。 Th1/Th2/Th17 相关细胞标志物的 mRNA 表达在 4.5 至 6 岁之间下降（P < 0.001）。结论 6 岁时，Treg 细胞随着农场暴露而减少，而哮喘患者则增加，与 4.5 岁时相反。这种免疫学转换定义了 6 岁之前 Treg 介导的通过环境暴露进行哮喘保护的关键时间窗口。
BackgroundFarm exposure protects against development of allergies early in life. At 4.5 years, protection against asthma by farm-milk exposure was partially mediated by regulatory T cells (Tregs). The aim of this study was to investigate the critical time window of the asthma-protective' farm effect via Tregs during childhood immune maturation.MethodsTregs were assessed longitudinally at 4.5 and 6 years in 111 children (56 farm and 55 reference children) from the PASTURE/EFRAIM birth cohort (flow cytometry). Peripheral blood mononuclear cells were cultured unstimulated (U), with phorbol 12-myristate 13-acetate/ionomycin (PI) or lipopolysaccharide (LPS), and stained for Tregs (CD4(+)CD25(high)FOXP3(upper20%)). mRNA expression of Treg/Th1/Th2/Th17-associated cell markers was measured ex vivo. Suppressive capacity of Tregs on effector cells and cytokines was assessed. Detailed questionnaires assessing farm exposures and clinical phenotypes from birth until age 6 years were answered by the parents.ResultsTreg percentage before and after stimulation and FOXP3mRNA expression ex vivo decreased from age 4.5 to 6 years (P(U,LPS) < 0.001; P(PI) = 0.051; P(FOXP3) < 0.001). High vs low farm-milk and animal-stable exposure was associated with decreased LPS-stimulated Treg percentage at age 6 years (P(LPS) = 0.045). Elevated LPS-stimulated-Treg percentage at age 6 was associated with increased risk of asthma (aOR = 11.29, CI: 0.96-132.28, P = 0.053). Tregs from asthmatics vs nonasthmatics suppressed IFN- (P = 0.015) and IL-9 (P = 0.023) less efficiently. mRNA expression of Th1/Th2/Th17-associated cell markers decreased between 4.5 and 6 years (P < 0.001).ConclusionsTregs at the age of 6 years were decreased with farm exposure and increased within asthmatics, opposite to age 4.5 years. This immunological switch defines a critical time window' for Treg-mediated asthma protection via environmental exposure before age 6 years.