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.
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The authors thank S. Hedrick and C. Burns for their valuable suggestions and discussion.
R.J.N. is an inventor on patent applications (10035857, 9631018, 9217035, 8501915, 8465740, 8236304 and 8231872) submitted by Dartmouth College, and patent applications (9890215 and 9381244) submitted by Kings College London and Dartmouth College and is a co-founder of ImmuNext, a company involved in the development of VISTA-related assets. These applications cover the use of VISTA targeting for modulation of the immune response. M.A.E. declares no competing interests.
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ElTanbouly, M.A., Noelle, R.J. Rethinking peripheral T cell tolerance: checkpoints across a T cell’s journey. Nat Rev Immunol (2020). https://doi.org/10.1038/s41577-020-00454-2