Immunobiology, Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
Eur J Immunol. 2014 Dec;44(12):3614-20. doi: 10.1002/eji.201444879. Epub 2014 Oct 27.
ATP-binding cassette (ABC) transporters, including ABC-transporter B1 (ABCB1), extrude drugs, metabolites, and other compounds (such as mitotracker green (MTG)) from cells. Susceptibility of CD4(+) regulatory T (Treg) cells to the ABCB1-substrate cyclophosphamide (CPA) has been reported. Here, we characterized ABCB1 expression and function in human CD4(+) T-cell subsets. Naïve, central memory, and effector-memory CD4(+) T cells, but not Treg cells, effluxed MTG in an ABCB1-dependent manner. In line with this, ABCB1 mRNA and protein was expressed by nonregulatory CD4(+) T-cell subsets, but not Treg cells. In vitro, the ABCB1-substrate CPA was cytotoxic for Treg cells at a 100-fold lower dose than for nonregulatory counterparts, and, inversely, verapamil, an inhibitor of ABC transporters, increased CPA-toxicity in nonregulatory CD4(+) T cells but not Treg cells. Thus, Treg cells lack expression of ABCB1, rendering them selectively susceptible to CPA. Our findings provide mechanistic support for therapeutic strategies using CPA to boost anti-tumor immunity by selectively depleting Treg cells.
三磷酸腺苷结合盒（ABC）转运蛋白，包括 ABC 转运蛋白 B1（ABCB1），将药物、代谢物和其他化合物（如米托蒽醌绿（MTG））从细胞中排出。已经报道了 CD4(+) 调节性 T（Treg）细胞对 ABCB1 底物环磷酰胺（CPA）的敏感性。在这里，我们描述了 ABCB1 在人 CD4(+) T 细胞亚群中的表达和功能。幼稚、中央记忆和效应记忆 CD4(+) T 细胞，但不是 Treg 细胞，以 ABCB1 依赖性方式排出 MTG。与此一致，非调节性 CD4(+) T 细胞亚群表达 ABCB1 mRNA 和蛋白，但 Treg 细胞不表达。在体外，ABCB1 底物 CPA 对 Treg 细胞的细胞毒性比非调节性对照细胞低 100 倍，相反，ABC 转运蛋白抑制剂维拉帕米增加了非调节性 CD4(+) T 细胞而非 Treg 细胞中 CPA 的细胞毒性。因此，Treg 细胞缺乏 ABCB1 的表达，使其对 CPA 具有选择性敏感性。我们的发现为使用 CPA 通过选择性耗尽 Treg 细胞来增强抗肿瘤免疫的治疗策略提供了机制支持。
