The maintenance of human CD4+CD25+ regulatory T cell function:: IL-2, IL-4, IL-7 and IL-15 preserve optimal suppressive potency in vitro
The maintenance of human CD4+CD25+ regulatory T cell function:: IL-2, IL-4, IL-7 and IL-15 preserve optimal suppressive potency in vitro
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DOI：
10.1093/intimm/dxm047
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发表时间：
2007-06-01
影响因子：
4.4
通讯作者：
Garden, O. A.
中科院分区：
文献类型：
--
作者：
Yates, John;Rovis, Flavia;Garden, O. A.
CD 4 + CD 25+调节性T细胞（TCRs）具有深远的免疫学应用，其实现将需要更好地理解在离体操作期间影响其功能和表型的因素。在鼠模型中，IL-2在体内维持功能性Treg群体和体外激活抑制中起重要作用。我们已经发现IL-2在体外维持人CD 4 + CD 25 + T细胞的最佳功能，并增加叉头盒蛋白3、人命名法（FOXP 3）和独特标志物CD 25、细胞毒性T淋巴细胞抗原-4（CTLA-4）和糖皮质激素诱导的肿瘤坏死因子受体超家族成员18号（GITR）的表达。虽然IL-2减少自发凋亡的THEORY，这个属性本身不能解释的最佳维护的监管表型。磷脂酰肌醇3-激酶（PI 3 K）的化学抑制剂LY 294002抑制PI 3 K信号传导，消除了IL-2的最大抑制效力的维持，但对FOXP 3，CD 25，CTLA-4和GITR的上调没有影响。其他常见的γ链（γ（c））细胞因子-IL-4、IL-7和IL-15-具有相似的性质，尽管IL-4显示出独特的对FOXP 3或Treg标记物表达的缺乏作用，尽管维持最大的调节功能。综上所述，我们的数据表明了一种模型，其中细胞因子IL-2，IL-4，IL-7和IL-15以PI 3 K依赖性方式维持人CD 4 + CD 25 + T细胞的最佳调节功能，为体外有效操纵Tcl 3提供了新的见解。
CD4+CD25+ regulatory T cells (Tregs) have far-reaching immunotherapeutic applications, the realization of which will require a greater understanding of the factors influencing their function and phenotype during ex vivo manipulation. In murine models, IL-2 plays an important role in both the maintenance of a functional Treg population in vivo and the activation of suppression in vitro. We have found that IL-2 maintains optimal function of human CD4+CD25+ Tregs in vitro and increases expression of both forkhead box protein 3, human nomenclature (FOXP3) and the distinctive markers CD25, cytotoxic T lymphocyte antigen-4 (CTLA-4) and glucocorticoid-induced tumor necrosis factor receptor superfamily member number 18 (GITR). Although IL-2 reduced spontaneous apoptosis of Tregs, this property alone could not account for the optimal maintenance of the regulatory phenotype. The inhibition of phosphatidylinositol 3-kinase (PI3K) signaling by LY294002, a chemical inhibitor of PI3K, abolished the maintenance of maximal suppressive potency by IL-2, yet had no effect on the upregulation of FOXP3, CD25, CTLA-4 and GITR. Other common gamma chain (gamma(c)) cytokines-IL-4, IL-7 and IL-15-had similar properties, although IL-4 showed a unique lack of effect on the expression of FOXP3 or Treg markers despite maintaining maximal regulatory function. Taken together, our data suggest a model in which they, cytokines IL-2, IL-4, IL-7 and IL-15 maintain the optimal regulatory function of human CD4+CD25+ T cells in a PI3K-dependent manner, offering new insight into the effective manipulation of Tregs ex vivo.