Department of Microbiology and Immunology, University of Illinois - College of Medicine, Chicago, IL, USA.
Department of Microbiology and Immunology, University of Illinois - College of Medicine, Chicago, IL, USA.
Cell Immunol. 2019 May;339:41-49. doi: 10.1016/j.cellimm.2018.09.008. Epub 2018 Sep 29.
Self-tolerance, the state of unresponsiveness to self-tissues/antigens, is maintained through central and peripheral tolerance mechanisms, and a breach of these mechanisms leads to autoimmune diseases. Foxp3 + T-regulatory cells (Tregs) play an essential role in suppressing autoimmune response directed against self-antigens and thereby regulate self-tolerance. Natural Tregs are differentiated in the thymus on the basis of their higher TCR-affinity to self-antigens and migrate to the periphery where they maintain peripheral tolerance. In addition, extra-thymic differentiation of induced Tregs can occur in the periphery which can control abrupt immune responses under inflammatory conditions. A defect in Treg cell numbers and/or function is found to be associated with the development of autoimmune disease in several experimental models and human autoimmune diseases. Moreover, augmentation of Tregs has been shown to be beneficial in treating autoimmunity in preclinical models, and Treg based cellular therapy has shown initial promise in clinical trials. However, emerging studies have identified an unstable subpopulation of Tregs which expresses pro-inflammatory cytokines under both homeostatic and autoimmune conditions, as well as in ex vivo cultures. In addition, clinical translation of Treg cellular therapy is impeded by limitations such as lack of easier methods for selective expansion of Tregs and higher cost associated with GMP-facilities required for cell sorting, ex vivo expansion and infusion of ex vivo expanded Tregs. Here, we discuss the recent advances in molecular mechanisms regulating Treg differentiation, Foxp3 expression and lineage stability, the role of Tregs in the prevention of various autoimmune diseases, and critically review their clinical utility for treating human autoimmune diseases.
自身耐受是指机体对自身组织/抗原无反应的状态，通过中枢和外周耐受机制得以维持，而这些机制的破坏会导致自身免疫性疾病。Foxp3+调节性 T 细胞（Tregs）在抑制针对自身抗原的自身免疫反应方面发挥着重要作用，从而调节自身耐受。天然 Tregs 在胸腺中根据其对自身抗原更高的 TCR 亲和力进行分化，并迁移到外周，在外周维持外周耐受。此外，诱导性 Tregs 可在外周发生额外的胸腺外分化，可在炎症条件下控制突然的免疫反应。在几种实验模型和人类自身免疫性疾病中发现 Treg 细胞数量和/或功能缺陷与自身免疫性疾病的发展有关。此外，在临床前模型中，增强 Tregs 已被证明对治疗自身免疫有益，基于 Treg 的细胞疗法在临床试验中也显示出初步的前景。然而，新兴的研究已经确定了 Tregs 的一个不稳定亚群，该亚群在稳态和自身免疫条件下以及在体外培养中表达促炎细胞因子。此外，Treg 细胞疗法的临床转化受到限制，例如缺乏更简单的方法来选择性扩增 Tregs，以及与细胞分选、体外扩增和输注体外扩增的 Tregs 所需的 GMP 设施相关的更高成本。在这里，我们讨论了调节 Treg 分化、Foxp3 表达和谱系稳定性的分子机制的最新进展，Tregs 在预防各种自身免疫性疾病中的作用，并批判性地审查了它们在治疗人类自身免疫性疾病方面的临床应用。
