Biology

Cytotoxic T cell

Apoptosis

In vitro

Immunology

T cell

Peripheral tolerance

Immune tolerance

Programmed cell death

Cell biology

Senescence

Genetics

Immune system

Nature reviews. Immunology

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. A number of T cell-intrinsic peripheral tolerance mechanisms (quiescence, ignorance, anergy, exhaustion, senescence and cell death) restrain autoimmunity and overactive immune responses. Here, the authors provide an integrated perspective of peripheral T cell tolerance by comparing the molecular mechanisms that govern these checkpoints and discussing their role in T cell tolerance and fate regulation.

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