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  • Review Article
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Life and death in peripheral T cells

Nature Reviews Immunology volume 7, pages 532–542 (2007)Cite this article

Key Points

  • T cells can die by several mechanisms: by extrinsic cell-death-receptor- and caspase-dependent apoptosis, by intrinsic mitochondria- and caspase-dependent apoptosis, or by caspase-independent cell death, for example by the activation of cathepsins.

  • T-cell survival is influenced through triggering of the T-cell receptor (TCR) and co-stimulatory molecules (including CD28) and adhesion molecules, as well as through cytokines, such as interleukin-2 (IL-2), IL-13 and IL-15.

  • The extrinsic apoptotic pathway is triggered by signals emanating from the cell-surface death receptors triggered by cell-death-receptor ligands, such as tumour-necrosis factor (TNF), CD95 ligand (CD95L; also known as FASL) and TNF-related apoptosis-inducing ligand (TRAIL). Upon stimulation of cell-death receptors a large protein complex is formed proximal to the cell membrane, known as the death-inducing signalling complex (DISC). The CD95 DISC consists of oligomerized (probably trimerized) CD95, the death-domain-containing adaptor molecule FAS-associated death domain (FADD), two isoforms of pro-caspase-8, pro-caspase-10 and the cellular caspase-8 (FLICE)-like inhibitory protein (cFLIP) proteins.

  • cFLIP acts at the DISC as an inhibitor of cell-death-receptor signalling, and has an important role in determining life and death of T cells. Here, we discuss diverse and new cFLIP molecules, cFLIP splice variants and cleavage products. cFLIP proteins have various functions; they influence the extrinsic cell-death-receptor-mediated pathway and inhibit apoptosis at the DISC. In addition, cFLIP cleavage products, such as p22-FLIP, also activate nuclear factor-κB (NF-κB), which leads to proliferation.

  • Haematopoietic progenitor kinase 1 (HPK1) regulates T-cell life and death by activating or suppressing NF-κB. Conversion of full-length HPK1 by caspase-3 cleavage during expansion of peripheral T cells leads to inhibition of NF-κB and sensitization towards cell death.

Abstract

During the course of an immune response, antigen-reactive T cells clonally expand and then are removed by apoptosis to maintain immune homeostasis. Life and death of T cells is determined by multiple factors, such as T-cell receptor triggering, co-stimulation or cytokine signalling, and by molecules, such as caspase-8 (FLICE)-like inhibitory protein (FLIP) and haematopoietic progenitor kinase 1 (HPK1), which regulate the nuclear factor-κB (NF-κB) pathway. Here, we discuss the concepts of activation-induced cell death (AICD) and activated cell-autonomous death (ACAD) in the regulation of life and death in T cells.

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Figure 1: Life and death of T cells.
Figure 2: CD95 DISC and activation of pro-caspase-8 at the CD95 DISC.
Figure 3: Intrinsic apoptotic pathway in T cells.
Figure 4: Overview of cFLIP isoforms and cleavage products.
Figure 5: Regulation of NF-κB activation by cFLIP.
Figure 6: The role of HPK1 and HPK1-C in the regulation of AICD.

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Acknowledgements

We thank E. Suri-Payer, A. Golks, D. Brenner, K. Gülow and B. Kyewski for critical reading and comments, H. Sauter for excellent secretarial work, the Deutsche Krebshilfe, the Wilhelm Sander Stiftung, the SFB 405 and the Tumourzentrum Heidelberg/Mannheim for supporting our work.

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  1. Tumour Immunology Program, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg, D-69120, Germany

    Peter H. Krammer, Rüdiger Arnold & Inna N. Lavrik

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  1. Peter H. Krammer
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  2. Rüdiger Arnold
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Correspondence to Peter H. Krammer.

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Glossary

Cathepsins

Proteases that are mostly located in lysosomes and lysosome-like organelles and can be divided into cysteine, aspartate and serine cathepsin subgroups according to their active-site amino acid.

Activation-induced cell death

(AICD). A process in which activated Tcell-receptor-restimulated T cells undergo cell death after engagement of cell-death receptors, such as CD95 or the tumour-necrosis factor receptor (TNFR), or after exposure to reactive oxygen species (ROS).

Caspases

A family of cytosolic proteases that contain a cysteine residue in the active site and that cleave their substrate after an aspartic-acid residue. Initiator caspases are typically activated in response to particular stimuli: for example, caspase-8 is activated after cell-death-receptor ligation, caspase-9 after apoptosome activation, and caspase-2 after DNA damage. Effector caspases (such as caspase-3, caspase-6 and caspase-7) are activated by initiator caspases and are particularly important for the ordered dismantling of vital cellular structures.

Zymogen

The inactive precursor of a protease. The zymogen contains an amino-terminal pro-domain that keeps the protease in an inactive state. The removal of the pro-domain by another protease or by autoproteolysis leads to a conformational change that exposes the active site.

Death domain

(DD). 80–100 residue long motifs involved in the transduction of the apoptotic signal. The DD superfamily consists of the DD subfamily itself, the death-effector domain (DED) subfamily and the caspase recruitment domain (CARD) subfamily.

Apoptosome

A complex that forms when cytochrome c is released from mitochondria and interacts with the cytosolic protein apoptotic-protease-activating factor 1 (APAF1), which in turn recruits pro-caspase-9. In the presence of ATP, this interaction results in the allosteric activation of caspase9 and of downstream effectors, caspase-3, caspase-6 and caspase-7.

'Helpless' CD8+ T cells

A distinct subset of CD8+ T cells that have undergone activation without additional stimulation ('help') by CD4+ T cells.

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Krammer, P., Arnold, R. & Lavrik, I. Life and death in peripheral T cells. Nat Rev Immunol 7, 532–542 (2007). https://doi.org/10.1038/nri2115

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