Key Points
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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.
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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.
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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.
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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.
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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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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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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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DOI: https://doi.org/10.1038/nri2115
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Peptidylarginine deiminase 2 promotes T helper 17-like T cell activation and activated T cell-autonomous death (ACAD) through an endoplasmic reticulum stress and autophagy coupling mechanism
Cellular & Molecular Biology Letters (2022)
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Mucosal-associated invariant T cells predict increased acute graft-versus-host-disease incidence in patients receiving allogeneic hematopoietic stem cell transplantation
Cancer Cell International (2022)
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Mitochondrial reactive oxygen is critical for IL-12/IL-18-induced IFN-γ production by CD4+ T cells and is regulated by Fas/FasL signaling
Cell Death & Disease (2022)