Department of Microbiology and Immunology, Geisel School of Medicine, Norris Cotton Cancer Center, Dartmouth College, Hanover, NH, USA.
Nat Rev Immunol. 2021 Apr;21(4):257-267. doi: 10.1038/s41577-020-00454-2. Epub 2020 Oct 19.
Following their exit from the thymus, T cells are endowed with potent effector functions but must spare host tissue from harm. The fate of these cells is dictated by a series of checkpoints that regulate the quality and magnitude of T cell-mediated immunity, known as tolerance checkpoints. In this Perspective, we discuss the mediators and networks that control the six main peripheral tolerance checkpoints throughout the life of a T cell: quiescence, ignorance, anergy, exhaustion, senescence and death. At the naive T cell stage, two intrinsic checkpoints that actively maintain tolerance are quiescence and ignorance. In the presence of co-stimulation-deficient T cell activation, anergy is a dominant hallmark that mandates T cell unresponsiveness. When T cells are successfully stimulated and reach the effector stage, exhaustion and senescence can limit excessive inflammation and prevent immunopathology. At every stage of the T cell's journey, cell death exists as a checkpoint to limit clonal expansion and to terminate unrestrained responses. Here, we compare and contrast the T cell tolerance checkpoints and discuss their specific roles, with the aim of providing an integrated view of T cell peripheral tolerance and fate regulation.
T 细胞从胸腺迁出后，获得了强大的效应功能，但必须避免宿主组织受到伤害。这些细胞的命运由一系列调节 T 细胞介导的免疫质量和幅度的检查点决定，称为耐受检查点。在本观点中，我们讨论了控制 T 细胞整个生命周期中六个主要外周耐受检查点的介质和网络：静止、无知、无能、衰竭、衰老和死亡。在幼稚 T 细胞阶段，两个主动维持耐受的内在检查点是静止和无知。在缺乏共刺激的 T 细胞激活的情况下，无能是 T 细胞无反应性的主要特征。当 T 细胞被成功激活并达到效应阶段时，衰竭和衰老可以限制过度炎症并防止免疫病理。在 T 细胞旅程的每个阶段，细胞死亡作为一个检查点存在，以限制克隆扩增并终止不受控制的反应。在这里，我们比较和对比了 T 细胞耐受检查点，并讨论了它们的特定作用，旨在提供 T 细胞外周耐受和命运调节的综合观点。
