Following TRAIL's path in the immune system

Abstract

The members of the tumour necrosis factor (TNF) superfamily of cytokines play important roles in the regulation of various immune-cell functions. Likewise, induction of cell death by apoptosis is indispensable for the normal functioning of the immune system. There are two major pathways of apoptosis induction. The intrinsic, or mitochondrial, pathway is regulated by the activation and interaction of members of the Bcl-2 family. The extrinsic, or death receptor, pathway is triggered by certain TNF family members when they engage their respective cognate receptors on the surface of the target cell. Hence, cell-to-cell-mediated death signals are induced by activation of these death receptor-ligand systems. Besides TNF itself and the CD95 (Fas/APO-1) ligand (FasL/Apo1L), the TNF-related apoptosis-inducing ligand (TRAIL/Apo2L) belongs to the subfamily of ligands that is responsible for extrinsic induction of cell death. Depending on their status of stimulation, TRAIL can be expressed by various cells of the immune system, amongst them natural killer (NK) cells, T cells, natural killer T cells (NKT cells), dendritic cells and macrophages. TRAIL has been implicated in immunosuppressive, immunoregulatory and immune-effector functions. With respect to pathological challenges, TRAIL and its receptors have been shown to play important roles in the immune response to viral infections and in immune surveillance of tumours and metastases. In this review we summarize the current knowledge on the role of TRAIL and its receptors in the immune system and, based on this, we discuss future directions of research into the diverse functions of this fascinating receptor-ligand system.

Figure 1

Schematic overview of the human tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) apoptosis pathway. Binding of TRAIL to TRAIL-R1 and/or TRAIL-R2 leads to receptor trimerisation and formation of the death-inducing signalling complex (DISC). The adaptor protein Fas-associated death domain (FADD) is recruited to the DISC where the death domains (DD) of both proteins interact. Subsequently, pro-caspases 8 and 10 are recruited to the DISC where they interact with FADD via their death effector domains (DEDs). DISC-activated caspases 8 and 10 then trigger a caspase cascade by cleavage of caspase-3. In addition, Bid is cleaved into tBid, which initiates the mitochondrial apoptosis pathway leading to release of cytochrome c (CytC) and second mitochondria derived activator of caspases/direct IAP binding protein with low pI (Smac/DIABLO) from the mitochondria. CytC, together with apoptotic protease activating factor 1 (Apaf-1) forms the apoptosome, an activation platform for caspase-9. Smac/Diablo counteracts the inhibitory function of X-linked inhibitor of apoptosis protein (XIAP), thereby allowing for full activation of caspases 3 and 9, ultimately leading to cell death. The intrinsic, Bcl-2-controlled, pathway is also triggered after extensive DNA damage. BH3-only proteins PUMA and Noxa are up-regulated, thereby altering the ratio of pro-apoptotic and anti-apoptotic Bcl-2-family members, allowing for mitochondrial depolarization and cell death. c-FLIP, cellular FLICE inhibitory protein.

Figure 2

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) in T-cell homeostasis and differentiation. (a) So-called ‘helpless’ CD8⁺ T cells that are primed in the absence of CD4⁺ T-cell help are unable to undergo a second round of clonal expansion upon restimulation with their cognate antigen because they are eliminated by activation-dependent killing via TRAIL., By contrast, ‘helped’ CD8⁺ T cells are resistant to TRAIL-induced apoptosis, probably as a result of IL-15. (b) After stimulation with anti-CD3, T helper 0 (Th0) cells can differentiate into T helper 1 (Th1) cells in the presence of interleukin (IL)-12 or into T helper 2 (Th2) cells in the presence of IL-4. Th1 cells express CD95L, whereas Th2 cells up-regulate TRAIL on their surface. Th1 cells can then be killed by TRAIL, whereas Th2 cells are resistant to TRAIL-induced apoptosis, possibly as a result of the up-regulation of cellular FLICE inhibitory protein (c-FLIP) in Th2 cells.,

Figure 3

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated killing of virally infected cells depends on type I and II interferons (IFNs). Virus infection leads to upregulation of TRAIL-R1 and TRAIL-R2 on the surface of the infected cell. In addition, IFN-α and IFN-β are produced. These type I IFNs, together with IFN-γ, which is autocrinely produced by activated CD8⁺ cytotoxic lymphocytes (CTLs) cause the upregulation of TRAIL on CTLs, which can, in turn, kill the virus-infected cell via TRAIL.–