Ex vivo expansion of CD4+CD25+FoxP3+ T regulatory cells based on synergy between IL-2 and 4-1BB signaling
Ex vivo expansion of CD4+CD25+FoxP3+ T regulatory cells based on synergy between IL-2 and 4-1BB signaling
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DOI：
10.4049/jimmunol.179.11.7295
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发表时间：
2007-12-01
影响因子：
4.4
通讯作者：
Shirwan, Haval
中科院分区：
文献类型：
--
作者：
Elpek, Kutlu G.;Yolcu, Esma S.;Shirwan, Haval
天然存在的CD 4（+）CD 25（+）FoxP 3（+）T调节性（Treg）细胞需要通过TCR、CD 28和IL-2 R转导的三种不同信号用于其发育和维持。这些要求作为最近开发的几种离体扩增方案的基础，所述方案依赖于在高剂量IL-2存在下使用固体支持物结合的抗CD 3和CD 28的Ab。我们在这项研究中报告，Treg细胞上调诱导型共刺激受体4-1BB的表达，以响应IL-2，和刺激使用这种受体通过一种新形式的4-1BB配体（4-1BBL）融合到一种修饰形式的核心链霉亲和素（SA-4-1BBL）是有效的，在3周内扩大这些细胞高达110倍。扩增的细胞上调CD 25、4-1BB和膜TGF-β，抑制T细胞增殖，并防止同种异体胰岛过继转移到移植受体后的排斥反应。重要的是，SA-4-1BBL使CD 4（+）CD 25（-）T效应细胞对Treg细胞的抑制反应不敏感。这种通过4-1BB信号传导的双重功能，维斯于Treg细胞扩增和许可对Treg细胞抑制具有抗性的T效应细胞，以及IL-2对4-1BB的上调，可以作为抗原攻击后免疫稳态的重要调节机制。使用可溶形式的SA-4-1BBL的刺激代表了扩增Treg细胞的新方法，其在自身免疫和移植中具有潜在的治疗应用。
Naturally occurring CD4(+)CD25(+)FoxP3(+) T regulatory (Treg) cells require three distinct signals transduced via TCR, CD28, and IL-2R for their development and maintenance. These requirements served as the basis for several recently developed ex vivo expansion protocols that relied on the use of solid support-bound Abs to CD3 and CD28 in the presence of high dose IL-2. We report in this study that Treg cells up-regulate the expression of inducible costimulatory receptor 4-1BB in response to IL-2, and stimulation using this receptor via a novel form of 4-1BB ligand (4-1BBL) fused to a modified form of core streptavidin (SA-4-1BBL) was effective in expanding these cells up to 110-fold within 3 wk. Expanded cells up-regulated CD25, 4-1BB, and membranous TGF-beta, suppressed T cell proliferation, and prevented the rejection of allogeneic islets upon adoptive transfer into graft recipients. Importantly, SA-4-1BBL rendered CD4(+)CD25(-) T effector cells refractive to suppression by Treg cells. This dual function of signaling via 4-1BB, vis-A-vis Treg cell expansion and licensing T effector cells resistant to Treg cell suppression, as well as the up-regulation of 4-1BB by IL-2 may serve as important regulatory mechanisms for immune homeostasis following antigenic challenge. Stimulation using a soluble form of SA-4-1BBL represents a novel approach to expand Treg cells with potential therapeutic applications in autoimmunity and transplantation.