Rethinking peripheral T cell tolerance: checkpoints across a T cell's journey

Abstract

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.

Fig. 1 |. Integrated road map for T cell tolerance checkpoints.

Temporal schematic integrating the tolerance checkpoints at each stage of the peripheral T cell lifespan. Six tolerance checkpoints exist and integrate to regulate T cell responses at all stages. These T cell regulatory checkpoints start at the naive T cell stage, where quiescence and ignorance enforce T cell tolerance. These checkpoints occur before T cell activation by cognate antigen encounter and priming. After antigen-specific T cell activation, co-stimulation-deficient T cell receptor (TCR) signalling can trigger anergy, which enforces T cell hyporesponsiveness and limits T cell responses to inappropriate stimuli (such as self-antigens). Such tolerogenic activation can also induce peripheral T cell deletion, known as tolerance-induced cell death. As a result of chronic antigen stimulation during the effector T cell stage, exhaustion and senescence can limit T cell responses. During the effector stage and beyond (where terminal effector T cells undergo clonal contraction), restimulation-induced cell death and cytokine withdrawal-induced cell death serve to terminate T cell responses.