In autoimmunity, the important and fragile balance between immunity and tolerance is disturbed, resulting in abnormal immune responses to the body’s own tissues and cells. CD4⁺CD25^hiFoxP3⁺ regulatory T cells (Tregs) induce peripheral tolerance in vivo by means of direct cell–cell contact and release of soluble factors, or indirectly through antigen-presenting cells (APC), thereby controlling auto-reactive effector T cells. Based on these unique capacities of Tregs, preclinical studies delivered proof-of-principle for the clinical use of Tregs for the treatment of autoimmune diseases. To date, the first clinical trials using ex vivo expanded polyclonal Tregs have been completed. These pioneering studies demonstrate the feasibility of generating large numbers of polyclonal Tregs in a good manufacturing practices (GMP)-compliant manner, and that infusion of Tregs is well tolerated by patients with no evidence of general immunosuppression. Nonetheless, only modest clinical results were observed, arguing that a more antigen-specific approach might be needed to foster a durable patient-specific clinical cell therapy without the risk for general immunosuppression. In this review, we discuss current knowledge, applications and future goals of adoptive immune-modulatory Treg therapy for the treatment of autoimmune disease and transplant rejection. We describe the key advances and prospects of the potential use of T cell receptor (TCR)- and chimeric antigen receptor (CAR)-engineered Tregs in future clinical applications. These approaches could deliver the long-awaited breakthrough in stopping undesired autoimmune responses and transplant rejections.

在自身免疫中，免疫力和耐受力之间重要而脆弱的平衡被破坏，导致对人体自身组织和细胞的异常免疫反应。CD4 ⁺ CD25 ^hi FoxP3 ⁺调节性T细胞（Tregs）通过直接的细胞间接触和可溶性因子的释放，或通过抗原呈递细胞（APC）间接诱导体内耐受，从而控制自身反应性效应T细胞。基于Treg的这些独特能力，临床前研究为Treg在临床上治疗自身免疫性疾病的临床使用提供了原理证明。迄今为止，使用离体的首次临床试验扩展的多克隆Tregs已经完成。这些开创性研究证明，以符合良好生产规范（GMP）的方式生成大量多克隆Treg的可行性，并且没有一般免疫抑制作用的患者可以很好地耐受Treg的输注。但是，仅观察到了适度的临床结果，认为可能需要一种更具抗原特异性的方法来培养一种持久的针对患者的临床细胞疗法，而又没有普遍免疫抑制的风险。在这篇综述中，我们讨论过继免疫调节Treg治疗自体免疫疾病和移植排斥的当前知识，应用和未来目标。我们描述了关键的进展和潜在的T细胞受体（TCR）和嵌合抗原受体（CAR）工程的Treg在未来的临床应用中的潜在用途。这些方法可以在阻止不良的自身免疫反应和移植排斥反应方面实现期待已久的突破。