Abstract
T cells follow a triphasic distinct pathway of activation, proliferation and differentiation before becoming functionally and phenotypically “exhausted” in settings of chronic infection, autoimmunity and in cancer. Exhausted T cells progressively lose canonical effector functions, exhibit altered transcriptional networks and epigenetic signatures and gain constitutive expression of a broad coinhibitory receptor suite. This review outlines recent advances in our understanding of exhausted T cell biology and examines cellular and molecular mechanisms by which a state of dysfunction or exhaustion is established, and mechanisms by which exhausted T cells may still contribute to pathogen or tumour control. Further, this review describes our understanding of exhausted T cell heterogeneity and outlines the mechanisms by which checkpoint blockade differentially engages exhausted T cell subsets to overcome exhaustion and recover T cell function.
Highlights
T cells are important effector immune cells responsible for inducing cell death of virally transformed or malignant cells, after initiating a highly orchestrated program of differentiation
Given the recent evidence that T cell exhaustion can be rescued, it highlights the clinical relevance for understanding the molecular mechanisms driving it
In the case of chronic infections, exhausted T cells play an important role in controlling disease and, further, immunopathology
Summary
T cells are important effector immune cells responsible for inducing cell death of virally transformed or malignant cells, after initiating a highly orchestrated program of differentiation. On initial encounter with mature antigen-presenting cells (APC) bearing their cognate peptide epitope in secondary lymphoid organs, naïve CD8+ T cells integrate and accumulate a signal through their TCR/CD3 complex and associated adaptors, and through constitutively expressed co-stimulatory molecules of the CD28, SLAM and TNFRSF (expertly reviewed elsewhere) [1]. This initial “priming” stimulation is augmented by paracrine cytokine signalling from APC (for example interleukin (IL)-12 [2,3], or Type I interferons (IFN)) [4] and paracrine and autocrine IL-2 signalling [5] and allows T cells to initiate a program of rapid and extensive division and differentiation [6]. Under conditions of prolonged antigen exposure, this canonical naïve-effector-memory spectrum can be perturbed, and T cells instead follow a distinct pathway of differentiation and become functionally and phenotypically “exhausted”
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