Signalling Pathways of the Tnf Superfamily: a Double-Edged Sword

REVIEWS SIGNALLING PATHWAYS OF THE TNF SUPERFAMILY: A DOUBLE-EDGED SWORD Bharat B. Aggarwal Two different tumour-necrosis factors (TNFs), first isolated in 1984, were found to be cytotoxic to tumour cells and to induce tumour regression in mice. Research during the past two decades has shown the existence of a superfamily of TNF proteins consisting of 19 members that signal through 29 receptors. These ligands, while regulating normal functions such as immune responses, haematopoiesis and morphogenesis, have also been implicated in tumorigenesis, transplant rejection, septic shock, viral replication, bone resorption, rheumatoid arthritis and diabetes; so indicating their role as ‘double-edged swords’. These cytokines either induce cellular proliferation, survival, differentiation or apoptosis. Blockers of TNF have been approved for human use in treating TNF-linked autoimmune diseases in the United States and other countries. Similar to most discoveries in science, the discovery of time due to the crudeness of the preparations. Lympho- tumour-necrosis factor (TNF) is marked by a series toxin (LT) was described in 1968 by G. Granger and co- of important landmarks. More than a century ago, a workers9 as a protein that is produced by lymphocytes German physician, P.Bruns, reported the regression of that kills tumour cells. tumours in humans after bacterial infection1. This led Not until 1984, when my group purified the proteins W. Coley, an American oncologist, to use bacterial to homogeneity10,11, determined the amino-acid extracts (referred as Coley’s toxins) for the treatment of sequence11,12 and cloned the complementary DNA13,14, human cancers, with some success2. Gratia et al.3 were the true chemical identities of TNF and LT, and showed tumour regression by bacterial extracts in a their relationship revealed. Human LT was the first guinea-pig model. In 1944, Shear et al.4 isolated cytotoxic cytokine to be purified from a B-lymphoblas- lipopolysaccharide (LPS) from the bacterial extracts toid cell line10; its structure was determined by classic and showed that this was responsible for the tumour protein sequence methods11. Neutralization of LT activ- regression. G. Algire, a French scientist, showed that LPS ity by LT-specific antibodies led to the isolation of a sec- induces haemorrhagic necrosis of tumours by inducing ond cytotoxic factor from a human myeloid-cell line systemic hypotension, collapse of tumour vasculature, that was known as TNF12. The determination of the tumour-cell anorexia and cell death5. Subsequently, amino-acid sequence of TNF indicated that the two Cytokine Research Section, O’Malley et al.6 showed that the tumour regression proteins were homologous12. The binding of TNF to its Department of effects of LPS are not direct, but are mediated through receptor and its displacement by LT further confirmed Bioimmunotherapy, 15 University of Texas M. D. the induction of a factor in the serum; which they the functional homology between the two proteins . Anderson Cancer Center, named tumour-necrotizing factor6, renamed by L. Old’s This was perhaps the earliest indication of the existence 1515 Holcombe Boulevard, group as tumour-necrosis factor (TNF)7. Old and co- of a potential TNF superfamily. Once most of the pro- Box 143, Houston, workers originally reported7 that macrophages were the tein sequence was known, the cDNAs for LT and TNF Texas, USA. cellular source of this factor, but later they showed that a were isolated13,14. The sequence homology between e-mail: aggarwal@ 8 mdanderson.org B-lymphoblastoid cell line was also a source . This dis- these two proteins (30% amino-acid identity) and the doi:10.1038/nri1184 crepancy is typical of the confusion that occurred at the existence of common cell-surface receptors led to NATURE REVIEWS | IMMUNOLOGY VOLUME 3 | SEPTEMBER 2003 | 745 © 2003 Nature Publishing Group REVIEWS the renaming of TNF and LT to TNF-α and TNF-β, presence of a cysteine-rich domain (CRD) in the extracel- respectively. Soon after, mouse TNF-α was indepen- lular portion (FIG. 1). These include four decoy receptors, dently discovered as a factor that mediated LPS-induced known as DCR1, DCR2, DCR3 and osteoprotegerin wasting (cachexia) in mice by Beutler et al.16, and as a (OPG), which reduce the ligand signalling. The ligands myeloid differentiation factor by Takeda and co-work- for death receptor 6 (DR6), receptor expressed in lym- ers17. These two cytokines laid the foundation for the phoid tissues (RELT) and TROY have not yet been identi- isolation and identification of the larger family of fied. Whereas germline mutations in the extracellular cytokines, now known as the TNF superfamily (FIG. 1). domain of TNFR1 suppress the secretion of the receptor Considerable advances have been made during the past leading to a family of dominantly inherited autoinflam- two decades in our understanding of the biology and matory syndromes37, the secretion of OPG affects the reg- the clinical role of the TNF superfamily. This review ulation of bone density38. Receptors of the TNFR super- focuses on these developments. family are broadly divided into two groups. Those with the death domain are known as death receptors. The Characteristic features of ligands and receptors death domain is a region of approximately 80 amino-acid At present 19 different ligands have been identified that residues first identified independently by two different belong to the TNF superfamily. Unlike TNF and LT, the groups in the cytoplasmic domain of CD95 and TNFRs; ligands for FAS (CD95), CD27, CD30, CD40, 4-1BB, their deletion abolishes ligand-induced apoptosis21,39,40. OX40 and herpes-virus entry mediator (HVEM) were Interestingly, a TNFR that has a cysteine-rich region in its identified and cloned not by protein sequencing, but by extracellular portion and serine/threonine protein kinase direct expression-cloning strategies18–21. This involved activity in its cytoplasmic domain has been discovered the use of specific antibodies, and studies of ligand− in the maize plant41. This protein, known as CRINKLY4, receptor interactions or biological activity. The descrip- is a TNFR-like receptor and has kinase activity that is tion of the amino-acid sequences of several ligands and involved in maize epidermal differentiation. receptors of the superfamily led to the identification of Additionally, a conserved domain in the extracellular certain regions of homology. Instead of an expression- region of TNFR1 and TNFR2 has been identified that cloning strategy, the availability of human genome mediates specific ligand-independent assembly of recep- sequences led scientists to use homology searches to tor trimers42. This pre-ligand-binding assembly domain identify several additional members of the TNF super- (PLAD) is physically distinct from the domain that family. TNF-related apoptosis-inducing ligand (TRAIL), forms the main contacts with the ligand, but is required also known as APO2L, was identified independently by for the assembly of TNFR complexes that bind TNF and two different groups22,23, followed by the identification mediate signalling. Other members of the TNFR super- of receptor activator of nuclear factor-κB (NF-κB) lig- family, including TRAIL receptor 1 (TRAILR1) and and (RANKL), also known as TRANCE (TNF-related CD40, show similar homotypic associations. So, TNFRs activation-induced cytokine) or OPGL (osteoprotegerin and related receptors seem to function as preformed ligand)24−26, vascular endothelial cell-growth inhibitor complexes rather than as individual receptor subunits (VEGI), also known as TL1A27,28, and B-cell-activating that oligomerize after ligand binding. factor (BAFF)21,30, also known as β-lymphocyte stimula- The cellular expression patterns of various members tor (BLYS), all by similar approaches. Glucocorticoid- of the TNF ligands and receptors, are shown in TABLE 1. induced TNF receptor family receptor ligand (GITRL) Almost all of the TNF ligands are expressed by cells of was identified and cloned by using a glucocorticoid- the immune system, including B cells, T cells, NK cells, induced differential display technique31. Because numer- monocytes and dendritic cells, the only exception is ous groups discovered the same cytokine independently VEGI, which is expressed mainly by endothelial cells43. and simultaneously, numerous names exist for each TNF The TNFRs, however, are expressed by a wide variety of family member. cells. For example, no cell type in the body has yet been An intriguing feature of these ligands is that when found that does not express TNFR1, whereas expression certain ligands are shed, they inhibit the function of the of TNFR2 is mainly by immune cells and endothelial ligand–receptor complex. For example, whereas the cells. Numerous activities are assigned to TNF,perhaps membrane-bound CD95 ligand (CD95L) kills human because its receptors are expressed by all cell types. This peripheral-blood T cells, soluble CD95L blocks this might also account for the non-specific toxicity of TNF. killing36. The fact that some soluble ligands act as ago- Whereas most ligands bind to a single receptor, others nists whereas others act as antagonists is intriguing. bind to more than one. For example, TRAIL binds to Furthermore, the transmembrane expression of most as many as five receptors (DR4, DR5, DCR1, DCR2 of the TNF-superfamily members indicates that they and OPG), whereas BAFF binds to three receptors; are meant to act locally. Only under non-physiological transmembrane activator and cyclophilin

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