Life and death in peripheral T cells

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Abstract
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.