National Health Service Blood and Transplant, Oxford, United Kingdom.
Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
Front Immunol. 2020 May 19;11:685. doi: 10.3389/fimmu.2020.00685. eCollection 2020.
The control of peripheral immune responses by FOXP3 T regulatory (Treg) cells is essential for immune tolerance. However, at any given time, Treg frequencies in whole blood can vary more than fivefold between individuals. An understanding of factors that influence Treg numbers and migration within and between individuals would be a powerful tool for cellular therapies that utilize the immunomodulatory properties of Tregs to control pathology associated with inflammation. We sought to understand how season could influence Treg numbers and phenotype by monitoring the proportion of natural thymus-derived Tregs (nTregs) defined as (CD3CD4CD25FOXP3CD127 ) cells as a proportion of CD4 T cells and compared these to all FOXP3 Tregs (allTregs, CD3CD25FOXP3CD127 ). We were able to determine changes within individuals during 1 year suggesting an influence of season on nTreg frequencies. We found that, between individuals at any given time, nTreg/CD4 T cells ranged from 1.8% in February to 8.8% in the summer where median nTreg/CD4 in January and February was 2.4% (range 3.75-1.76) and in July and August was 4.5% (range 8.81-3.17) = 0.025. Importantly we were able to monitor individual nTreg frequencies throughout the year in donors that started the year with high or low nTregs. Some nTreg variation could be attributed to vitamin D status where normal linear regression estimated that an absolute increase in nTreg/CD4 by 0.11% could be expected with 10 nmol increase in serum 25 (OH) vitamin D3 ( = 0.005, 95% CI: 0.03-0.19). We assessed migration markers on Tregs for the skin and/or gut. Here cutaneous lymphocyte associated antigen (CLA) expression on CD25FOXP3CD4/CD4 was compared with the same population expressing the gut associated integrin, β7. Gut tropic CD25FOXP3β7Tregs/CD4 had similar dynamics to nTreg/CD4. Conversely, CD25FOXP3CLATregs/CD4 showed no association with vitamin D status. Important for cellular therapies requiring isolation of Tregs, the absolute number of β7CD4CD25FOXP3Tregs was positively associated with 25(OH)vitamin D3 ( = 0.0208, = 0.184, = 0.021) whereas the absolute numbers of CLACD4CD25FOXP3Tregs in the periphery were not influenced by vitamin D status. These baseline observations provide new opportunities to utilize seasonal variables that influence Treg numbers and their migratory potential in patients or donors.
FOXP3+ T 调节性（Treg）细胞对周围免疫反应的控制对于免疫耐受至关重要。然而，在任何给定的时间，个体之间全血中 Treg 的频率可能相差五倍以上。了解影响 Treg 数量和个体内部及个体之间迁移的因素将是一种强大的工具，可利用 Treg 的免疫调节特性来控制与炎症相关的病理。我们试图通过监测作为（CD3+CD4+CD25+FOXP3+CD127-）细胞的天然胸腺来源的 Treg（nTreg）的比例作为 CD4+ T 细胞的比例，并将其与所有 FOXP3+ Treg（allTregs，CD3+CD25+FOXP3+CD127+）进行比较，来了解季节如何影响 Treg 数量和表型。我们能够在 1 年内确定个体内的变化，表明季节对 nTreg 频率有影响。我们发现，在任何给定的时间，个体之间的 nTreg/CD4+ T 细胞范围从 2 月的 1.8%到 8 月的 8.8%，中位数 nTreg/CD4+ 在 1 月和 2 月为 2.4%（范围 3.75-1.76），在 7 月和 8 月为 4.5%（范围 8.81-3.17）（P=0.025）。重要的是，我们能够在年初具有高或低 nTreg 的供体中全年监测个体 nTreg 频率。一些 nTreg 的变化可以归因于维生素 D 状态，其中正常线性回归估计，血清 25（OH）维生素 D3 增加 10 nmol 可使 nTreg/CD4+增加 0.11%（ = 0.005，95%CI：0.03-0.19）。我们评估了 Treg 上的皮肤和/或肠道迁移标志物。在这里，与表达肠道相关整合素β7 的相同群体相比，CD25+FOXP3+CD4+/CD4+上的皮肤淋巴细胞相关抗原（CLA）表达进行了比较。肠道趋向性 CD25+FOXP3+β7+Treg/CD4+具有与 nTreg/CD4+相似的动力学。相反，CD25+FOXP3+CLA+Treg/CD4+与维生素 D 状态无关。对于需要分离 Treg 的细胞治疗来说很重要的是，β7+CD4+CD25+FOXP3+Treg/CD4+的绝对数量与 25（OH）维生素 D3 呈正相关（ = 0.0208， = 0.184， = 0.021），而外周血中 CLA+CD4+CD25+FOXP3+Treg/CD4+的绝对数量不受维生素 D 状态的影响。这些基线观察结果为利用影响 Treg 数量及其迁移潜力的季节性变量提供了新的机会，无论是在患者还是供体中。
