Department of Nephrology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
Immunol Lett. 2011 Oct 30;140(1-2):59-67. doi: 10.1016/j.imlet.2011.06.005. Epub 2011 Jun 23.
CD4(+)CD25(+) regulatory T cells (Tregs) have recently been the subject of intense research due to their strong immunosuppressive effect. Increasing evidence suggests that IL-15 plays an important role in Tregs biology. Nevertheless, the mechanism by which IL-15 performs this function remains to be fully elucidated. To address this question, we isolated Tregs from human peripheral blood, and utilized IL-15, dendritic cells (DCs), or DCs combined with IL-15, to examine the proliferation of Tregs and to explore related molecular mechanisms. Here, we show that IL-15 can induce the proliferation of Tregs in the presence of DCs. The induction is mediated by DCs presenting IL-15 in trans to Tregs. Simultaneously, DCs-derived IL-2, regulated by IL-15, may also play a supportive role. After IL-15 withdrawal, IL-15 trans-endosomal recycling in DCs contributes to the proliferation of Tregs. The activation of Akt, Erk1/2 and STAT(5), and the degradation of p27(kip1) may be involved in this process. These findings might explain the proliferation of Tregs in the absence of IL-2 in vivo and provide a novel method to achieve large-scale proliferation of Tregs in vitro in order to obtain cell numbers sufficient for immunotherapy.
CD4(+)CD25(+) 调节性 T 细胞 (Tregs) 因其强大的免疫抑制作用而成为当前研究的热点。越来越多的证据表明，IL-15 在 Tregs 生物学中发挥着重要作用。然而，IL-15 发挥此功能的机制仍有待充分阐明。为了解决这个问题，我们从人外周血中分离出 Tregs，并用 IL-15、树突状细胞 (DC) 或 DC 与 IL-15 联合，来检测 Tregs 的增殖，并探讨相关的分子机制。在这里，我们表明 IL-15 在 DC 存在的情况下可以诱导 Tregs 的增殖。这种诱导是通过 DC 以转染方式将 IL-15 呈递给 Tregs 介导的。同时，由 IL-15 调节的 DC 衍生的 IL-2 也可能发挥支持作用。在 IL-15 耗尽后，DC 中的 IL-15 经内体再循环有助于 Tregs 的增殖。该过程可能涉及 Akt、Erk1/2 和 STAT(5)的激活以及 p27(kip1)的降解。这些发现可能解释了体内缺乏 IL-2 时 Tregs 的增殖，并为体外获得足够数量的细胞进行免疫治疗而实现 Tregs 的大规模增殖提供了一种新方法。
