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Immunology. May 2005; 115(1): 1–20.
PMCID: PMC1782125

The intriguing biology of the tumour necrosis factor/tumour necrosis factor receptor superfamily: players, rules and the games

Abstract

The members of the tumour necrosis factor (TNF)/tumour necrosis factor receptor (TNFR) superfamily are critically involved in the maintenance of homeostasis of the immune system. The biological functions of this system encompass beneficial and protective effects in inflammation and host defence as well as a crucial role in organogenesis. At the same time, members of this superfamily are responsible for host damaging effects in sepsis, cachexia, and autoimmune diseases. This review summarizes recent progress in the immunbiology of the TNF/TNFR superfamily focusing on results obtained from animal studies using gene targeted mice. The different modes of signalling pathways affecting cell proliferation, survival, differentiation, apoptosis, and immune organ development as well as host defence are reviewed. Molecular and cellular mechanisms that demonstrate a therapeutic potential by targeting individual receptors or ligands for the treatment of chronic inflammatory or autoimmune diseases are discussed.

Keywords: TNF/TNFR-superfamily, gene targeting, organogenesis, inflammation, host defence, autoimmunity

Introduction

When lymphotoxin (LT) and tumour necrosis factor (TNF)/cachectin were first identified13 and subsequently their cDNAs cloned4 it eventually became evident that these two cytokines are the prototypic members of a gene superfamily that regulates essential biological functions in mammalians.5

With molecular biology techniques arising, many related proteins of both ligands and receptors have been identified. Membrane-bound and/or soluble ligands of the TNF superfamily interact with one or more specific, membrane bound or soluble receptors which together comprise the corresponding TNF receptor (TNFR) superfamily. The majority of the members of this TNF/TNFR superfamily is expressed by immune cells. Activation of the TNFR members via their ligands affects cell proliferation, survival, differentiation and apoptosis of responding cells.

These biological activities encompass beneficial effects for the host in inflammation and protective immune responses in infectious diseases as well as crucial roles in organogenesis of secondary lymphoid organs and the maintenance of lymphoid structures throughout the body. On the other hand, some members of the TNF/TNFR superfamily, especially TNF, can exert host damaging effects in sepsis, fever syndromes, cachexia as well as in autoimmune diseases (e.g. rheumatoid arthritis, psoriasis, inflammatory bowel disease).

The TNF superfamily ligands are type II transmembrane proteins (intracellular N-terminus) which are biologically active as self assembling, non covalent bound, trimers.6 Approximately 20–30% amino acid homology in their interacting protein interfaces are responsible for the assembly of the trimeric tertiary structure. The external surfaces of the ligand trimers have little similarity in sequence accounting for the individual receptor specificity.79 Some of these ligands, e.g. TNF, are active both as a membrane integrated and as a soluble form released from the cell membrane after proteolytic cleavage, mainly by metalloproteinases induced by various stimuli. Certain ligands are expressed only as soluble molecules, e.g. LTα; but may also be recruited to the cell membrane to form heterotrimeric membrane anchored complexes and thereby enhancing regulatory specificity and complexity.10

The TNF-like receptors are type I transmembrane proteins characterized by cysteine-rich domains (CRD) that are the hallmark of the TNFR superfamily. These pseudorepeats are defined by intrachain disulphides generated by highly conserved cysteine residues within the receptor chains.11 Significant variation in the number of CRD exist among the receptor family members, from B-cell activating factor receptor (BAFFR) with only a partial CRD, to TNFRI and TNFRII which exhibit the most common structure bearing three CRD and up to six CRDs found in CD30.

Currently more than 40 members of the TNF/TNFR superfamily (for overview see: http://www.gene.ucl.ac.uk/nomenclature/genefamily/tnftop.html) have been identified. Currently even more knowledge about TNF/TNFR family members and their central biological role in host defence, inflammation, apoptosis, autoimmunity and organogenesis is just emerging. Members of the TNF/TNFR superfamily are now important targets in therapies against human diseases such as autoimmune disorders, IBD, osteoporosis, and cancer.

Modes of signalling

During the years it became apparent that most members of the TNF superfamily interact with more than one receptor of the corresponding superfamily of cognate receptors. This cross-utilization of ligands and receptors suggested redundancy in the biological functions within this superfamily. However, genetic approaches, mainly by the use of gene targeted mouse strains it was possible to define the physiological function linked to individual ligands or receptors in more detail and it became clear that almost each receptor—ligand system of this TNF/TNFR superfamily appears to have a unique and non-redundant function.

Recent results suggest that some members of the TNFR superfamily (FAS, TNFRI and TNFRII) preassemble on the cell surface prior to ligand binding.12 The formation of the preassembled complexes on the cell surface requires an N-terminal amino acid domain including parts of the first CRD. This region termed PLAD for ‘preligand assembly domain’ is necessary and sufficient for self assembly of these receptors on the cell surface. The PLAD interactions are specific and allow only the formation of receptor-chain homotrimers, however, it has also been demonstrated that transplanting the PLAD of TNFRI onto TNFRII results in the assembly of heterotrimeric receptor complexes.12

Upon receptor stimulation some of the TNFR superfamily members are cleaved from the cell surface (e.g. TNFRII, 4-1BB) or directly expressed as soluble isoforms lacking the transmembrane domain (e.g. TNFRII, 4-1BB, and FAS) being still capable of binding its cognate ligand. This represents a cellular mechanism, presumably in pathophysiological conditions, to antagonize ligand induced receptor stimulation.13 Interestingly, a recent report describes the identification of an intracellularly expressed TNFRII isoform. This study demonstrates further evidence that this TNFRII isoform mediates ligand dependant intracellular signalling, thus providing an example for intracellular cytokine receptor activation.14

The ligands can also form membrane-integrated trimers (e.g. TNF, homologous to lymphotoxins exhibits inducible expression and competes with herpes simplex virus glycoprotein D for HVEM a receptor expressed on T cells (LIGHT)) and some observations suggest that these membrane-anchored ligands can transduce reverse signals into the ligand-expressing cell when engaging their cognate receptors.15,16 Intense investigations are ongoing to clarify the reverse signalling pathways and their biological significance.

Receptor activation by the TNF family ligands causes recruitment of several intracellular adaptor proteins which activate multiple signal transduction pathways. Based on their intracellular sequences the members of the TNFR superfamily can be classified into three major groups.17

The first group, including FAS (CD95), TNFRI, TNF-related apoptosis inducing ligand receptor 1 (TRAIL-R1) (DR4), TRAIL-R2 (DR5), TRAIL-R4 (DcR2), TNF-like receptor apoptosis mediating protein (TRAMP) (DR3), Ectodysplasin (EDA) receptor (EDAR) contains so called death domains (DD) in their cytoplasmic domains (Fig. 1). Activation of these receptors leads to recruitment of intracellular death domain containing adaptors such as FAS-associated death domain (FADD) and TNFR-associated death domain (TRADD).18,19 These molecules activate the caspase cascade and subsequently induce apoptosis. In contrast to FAS, TNFRI only signals cell death when protein synthesis is blocked. The activation of TNFRI induces the activation and transcription of inflammatory genes.20,21 This means that TNFRI signalling provides also a mechanism to protect cells from an apoptotic response. This is also reflected on a molecular level that TNFRI primarily recruits TRADD while FAS interacts with FADD. TRADD in turn can associate with TNFR-associated factor (TRAF)2, TRAF1 and receptor interacting protein (RIP) to activate the nuclear factor-κB (NF-κB) and Jun N-terminal kinase (JNK) pathways, which protect cells from apoptosis.22,23 Mice with a genetic deletion of RIP are unable to activate NF-κB in response to TNFRI stimulation leading to TNF induced apoptosis.24 TRAF-2 deficiency in turn led to the inability to activate the JNK pathway in response to TNF.25 Therefore, TNFRI activation leads to signalling complexes that activate both the apoptotic caspase cascade and the NF-κB and JNK anti-apoptotic pathways (Fig. 2a). This balance is regulated at numerous levels including regulation of receptor/ligand expression, soluble decoy receptor expression and anti-apoptotic ligand induction.26

Figure 1
The TNF/TNFR superfamily. The TNF-related ligands are shown in blue and arrows indicate interactions with their receptors. The ectodomains of the TNFR superfamily are shown in grey with the appropriate number of CRDs. Death domains within the cytoplasmic ...
Figure 2
(a)Signal transduction of TNFRI. After binding of TNF, TNFRI first recruits TNFR associated death domain (TRADD) as a platform adaptor and assembles alternative signalling complexes. One complex involves receptor interacting protein (RIP) and TNFR associated ...

To prevent ligand-independent activation of some death domain containing TNFR family members the silencer of death domains (SODD) proteins associate constitutively with TNFRI and DR3 but not to other death receptor family members such as FAS, DR4 and DR5.27 It had been put forward that SODD proteins bind to the DD of these receptors and inhibit the recruitment of TRADD. Upon ligand-induced receptor aggregation the association of SODD is disrupted allowing the binding of TRADD. However, genetic deletion of SODD revealed that no alteration in the activation of NF-κB was observed after stimulation with TNF or the activation of DR3 in SODD gene deficient cells. Furthermore, resistance to lipopolysaacharide (LPS) combined with or without d-galactosamine hydrochloride (LPS-D-GalN) challenge, and infection with Listeria monocytogenes all depending on a functional TNFRI signalling2830 was similar in wild-type and SODD deficient mice.31 These in vivo data do not support a unique role for SODD in the signalling pathway of TNFRI and DR3.

Further mechanisms to control the induction of apoptosis mediated by TNFR family members is achieved by targeting downstream caspases.32 Expression of inhibitors of apoptosis (IAPs) like IAP-1, IAP-2 and X-linked X-IAP specifically inactivate effector caspases33,34 and are up-regulated in an NF-κB-dependant manner.35

The second group of receptors, including TNFRII, CD27, CD 30, CD40, LTβR, OX40, 4-1BB, BAFFR, B-cell maturation antigen (BCMA), receptor activator of NF-κB (RANK), transmembrane activator and calcium-signal modulating cyclophilin ligand (CAML) interactor (TACI), Fn14, herpes virus entry mediator (HVEM), activation induced TNF-receptor (AITR), X-linked EDA-A2 receptor (XEDAR) and the member of the TNFR family (TROY) contain TNF-receptor associated factor (TRAF)-interacting motifs (TIMs) in their cytoplasmic domain (Fig. 1). Activation of TIM containing TNFR family members leads to the recruitment of TRAF family members and the subsequent activation of signal transduction pathways like NF-κB, JNK, p38, extracellular signal-related kinase (ERK) and phosphoinositide 3-kinase (PI3K).17

Until today six mammalian TRAFs (TRAF1 to TRAF6) have been identified. TRAFs are evolutionary conserved proteins with homologues found in Drosophila melanogaster and Caenorhabditis elegans.36 All TRAFs are characterized by a highly conserved motive the so called TRAF domain. This C-terminal protein domain mediates binding to the receptors, the formation of homo- and heterodimers and the interaction with a number of additional signalling molecules such as the NF-κB-inducing kinase (NIK),37 in contrast the N-terminal domain has been shown to bind the anti apoptotic adaptors cIAP1 and 2.38 Although TRAF molecules have no enzymatic activity they can induce several signal transduction pathways which regulate cellular processes ranging from proliferation and differentiation to cell death. Tremendous work has been done to investigate the different associations and binding specificities of TRAFs with members of the TIM-containing TNFR family members in order to identify TRAF-activated signal transduction pathways.17 One of the best described is the NF-κB pathway, which plays a central role in the biological functions mediated by a variety of TNFR family members.

The activation of NF-κB by TNF and other members of the TNFR superfamily is mediated through the recruitment of different TRAFs. For instance TRAF2 is recruited by TNFRI, whereas TRAF2, TRAF5 and TRAF6 are recruited by RANK to activate NF-κB by RANKL.39,40 Just how TRAF2 mediates NF-κB activation has not yet been established. TRAF2 has been shown to interact with NIK.41 Gene deletion studies, however, have indicated that NIK is not required for NF-κB activation by TNF but is required for NF-κB activation by the LTβR, CD40 and BAFFR.42,43

Interestingly there are some receptors of this family which are capable of activating two pathways simultaneously like TNFRI which activation leads to the induction of apoptosis and the activation of NF-κB. A recent report suggests that upon TNF binding, TNFRI is capable of translocating to lipid rafts and that this recruitment is essential for TNF mediated NF-κB activation. Furthermore this study provides in vitro evidence that interfering with lipid raft formation switches TNF signalling from NF-κB activation to apoptosis.20 Very recent data demonstrated that upon ligand binding the TNF-TNFRI ligand receptor complex internalizes (TNF-receptosomes) followed by recruitment of the adapter molecules TRADD, FADD and caspase 8 to establish the death inducing signalling complex (DISC). A TNFRI internalization domain (TRID) has been identified which is required for receptor endocytosis. This study provides furthermore evidence that TNFRI internalisation, DISC formation and subsequent induction of apoptosis are inseparable events44 (Fig. 2a).

On the other hand, there are also receptors like the LTβR, CD40 and BAFFR, which can activate NF-κB using an additional, alternative NF-κB pathway. This became evident by examination of the natural occurring aly/aly mouse which has a defect in the NF-κB-inducing kinase (NIK).45,46 The activation of the classical NF-κB pathway in response to TNF or bacterial lipopolysccharide (LPS) requires the phosphorylation of IκBs by the activation of the IkB-kinase (IKK) complex composed of IKKα, IKKβ and IKKγ, the latter also known as NEMO.47 The activation of IKKβ and RelA which controls the activation of inflammatory genes such as vascular adhesion molecule-1 (VCAM-1), mucosal addressin vascular cell adhesion molecule-1 (MAdCAM-1), membrane inflammatory protein (MIP)-1β and MIP-2. IKKα activates the alternative NF-κB signalling pathway which involves the activation of NIK, and the subsequent processing of the p100 precursor protein to generate active p52 followed by the translocation to the nucleus. Association of p52 with RelB induces the transcription of genes implicated in secondary lymphoid organogenesis and homeostasis such as secondary lymphoid tissue chemokine (SLC), B-lymphocyte chemoattractant (BLC) and Epstein Barr virus-induced molecule 1 ligand chemokine (ELC) and stromal derived factor-1 (SDF-1)48,49 (Fig. 2b).

The third group of receptors including TRAIL-R3 (DcR1), DcR3 and osteoprotegerin (OPG) do not contain signalling motifs but instead compete with the other two groups of receptors for their corresponding ligands (Fig. 1).

Organogenesis and maintenance of lymphoid microarchitecture

Over the last decade, since the discovery that LTα-, LTβ- and LTβR-deficient mice lack several types of peripheral lymphoid tissues such as Peyer's patches (PPs) and lymph nodes (LNs) the critical role of LT signalling in lymphoid tissue organisation has been clearly demonstrated.5052 Expression of surface LTαβ on CD45+/interleukin (IL)-7R+/CXCR5+ progenitor cells also termed inducer cells or lymphoid tissue inducing cells (LTIC) originating from the fetal liver is required for the development of LNs and PPs during embryogenesis.5355 The second cellular component in the assembly of PP anlagen are cells of mesenchymal origin termed organizer cells expressing such molecules like IL-7, LTβR and BLC that are complementary to the molecules expressed on LTICs.56 It has been shown that IL-7R stimulation induces the expression of LTαβ on LTICs, which in turn, via LTβR stimulation on the organizer cells, induces CXCL13 and moreover the expression of VCAM-1 and MadCAM-1.54

Because of the stimulating ability of these two cellular components the region in which these cells assemble expands autonomously. As clearly indicated by previous studies, LTαβ expression on LTICs can also be induced by receptor activator of nuclear factor κB (RANK);57 however, PP anlagen are formed normally in RANK-deficient mice.58

In addition it has also been shown that TNF is capable of inducing LTαβ expression on LTICs.57 This is supported by the observation that in TNFRI deficient mice PP formation is aberrant.30,59 Because no defect in organogenesis so far has been described for TNFRII-deficient mice, TNFRI seems to be the major receptor type for transducing TNF signals during organogenesis. Administration of a LTβR inhibitor (LTβR:Ig) during pregnancy leads to defects in both LN and PP development similar to those observed in LTβ-deficient mice.60,61 Injection of LTβR:Ig after birth or transgenic overexpression of LTβR:Ig postnatally revealed that the formation of LNs and PPs could not be disrupted at this stage.61,62 These results are consistent with the notion that PP and LN genesis occur only within a narrow time window during embryogenesis. It is interestingly to note that LN genesis but not PP genesis of LTα-deficient mice which lack LNs and PPs can be restored by systemically delivered soluble LTβR agonist.63 Recent results indicate that for the development of LNs and PPs LIGHT is not essential, however, in LIGHT/LTβ double-deficient mice a cooperative role for both ligands of the LTβR in the organogenesis of mesenterial LN can be demonstrated.64,65

It has been further demonstrated that PP anlagen are defective in common γ chain and Janus kinase-3 (Jak-3) as well as in IL-7Rα deficient mice indicating that the IL-7Rα signal is transmitted through the γ-chain/Jak-3 pathway.56,66 Accumulating evidence indicates that similar mechanisms are involved in the LN anlagen but the question remains how the higher order of architecture in these lymphoid tissues is initiated and maintained.

In secondary lymphatic tissues which are the primary locations for the generation of the humoral immune response co-ordinated trafficking of the immune cells is maintained by direct interaction of antigen-presenting cells (APCs) with T and B cells leading to germinal center formation, immunoglobulin class switch and affinity maturation of the antibody response. Results using genetically modified mice indicate that members of the TNFR superfamily, mainly TNF and LT are required for lymphoid organogenesis and are also crucial for the maintenance of these structures and the generation of humoral immune responses in the adult.67 It was proposed that LT expressed on B cells is the main contributor in the maintenance of an organized lymphoid structure.51 To address the specific contributions of TNF and/or LT by T or B cells in the maintainance of splenic microarchitecture bone marrow (BM) transfer experiments and tissue specific gene knock out mice were employed. Transfer of BM from wild type mice in LTα deficient recipients restored B-cell follicles, follicular dendritic cells (FDC) networks as well as antibody responses to T-cell specific antigens.51 The contrast transfer of BM cells from BCR knockout (ko) + LTβ ko cells or BCR ko + TNF ko cells in BCR ko recipients did not restore FDC development.68 These results are consistent with data obtained from B-cell specific LTβ-deficient mice. In these mice splenic microarchitecture was strongly affected and peanut agglutinin (PNA)-positive GC formation virtually absent. In contrast, normal splenic microarchitecture was observed in T-cell specific LTβ-deficient mice consistent with the results based on BM reconstitution experiments described above. No deficiency in B-cell follicles, FDC or GC formation could be detected.69 Importantly, LIGHT-deficient mice did not demonstrate defects in the structure of the secondary lymphatic organs and no additional defects in splenic microarchitecture when crossed to LTβ-deficient mice.65 These results suggest that the activation of the LTβR by LTαβ plays a dominant role in the maintenance of lymphoid structures. So far, studies employing mice with impaired TNFRI signalling either by using TNFRI-deficient mice, or mice expressing a TNFRI:Ig transgene revealed that TNF signalling is also critically required for FDC and GC maintenance.62,70 These observations are also supported by experiments using neutralizing anti-TNF antibodies.63

Taken together these studies revealed a critical role for B cells expressing LT and TNF in the formation of GCs and FDC in the spleen and in the generation of an humoral immune response to T-cell dependant antigens. Beside these profound defects in lymphoid microachitecture and subsequently in the humoral immune response in mice deficient for TNFRI, LTα, LTβ and LTβR other members of the TNFR superfamily seem also to be involved in these processes.5,71 CD40 signalling is crucial for T- and B-cell collaboration as humans and mice with defective genes for CD40 or CD40L are impaired in Ig class switching and GC formation.72,73 OX40 disruption leads to impaired humoral responses while APRIL deficient mice are impaired in immunoglobulin A (IgA) class switching.74,75

The role of the TNF/TNFR superfamily members in lymphoid organogenesis, spleen architecture and humoral immunoglobulin responses based on studies using gene targeted mice are summarized in Tables 1 and and2,2, respectively.

Table 1
Role of TNF/TNFR superfamily members in lymphoid organogenesis and immunoglobulin responses based on studies using gene targeted mice
Table 2
Role of TNF/TNFR superfamily members in spleen architecture based on studies using gene targeted mice

Host defence

Neutralizing TNF demonstrated that the host defence against pathogens is severely impaired in the absence of TNF.7679 By the use of gene-targeted mice it has been shown that TNFRI is essential for the survival of infections with intracellular bacteria such as Listeria monocytogenes, Mycobacterium tuberculosis, M. avium, and Salmonella typhimurium.30,80 TNFRI-deficient mice are incapable of controlling the replication of L. monocytogenes in phagocytes although the antimicrobial defence systems that generate reactive oxygen radicals (p47 phox/gp91phox) and reactive nitrogen intermediates (iNOS) are not defective in these mice. Interestingly the expression of TNFRI on BM derived cells is sufficient to control the infection.29 In a recent report Serbina and coworkers identified a TNF/iNOS producing dendritic cell subset (Tip-DCs) in the spleens of mice infected with L. monocytogenes. The absence of these Tip-DCs results in profound TNF and iNOS deficiencies and an inability to clear primary bacterial infection.81 Similarly, TNFRI-deficient mice infected with the intracellular parasites Leishmania major or Trypanosoma cruzi showed higher parasitaemia and mortality than control mice.82,83 A crucial role of TNFRI but not for TNFRII in murine toxoplasma induced disease has been further demonstrated.84 Recent results employing TNFRI and TNFRII double deficient mice demonstrated that TNFR signalling is required for T-cell dependant pulmonary inflammation and lung injury during pneumocystis pneumonia and that T cells use the TNFRI and TNFRII signalling pathway in response to an extracellular fungal pathogen.85

Studies in mouse infection models have clearly revealed that TNF is a crucial component of both the antibacterially protective and the inflammatory immune response to M. tuberculosis. TNF is necessary for optimal co-ordination of both the differentiation of specific T cells to secrete the appropriate T helper 1 (Th1) cytokines and the development of granulomas in with activated epithelioid macrophages restrict mycobacterial growth.86 During infection TNF increases the phagocytic ability of macrophages and enhances the killing of mycobacteria, particularly in concert with interferon-γ (IFN-γ).87 On the other hand TNF is crucial for the recruitment of inflammatory cells by stimulating chemokine and cell adhesion molecule production leading to the accumulation of focussed mononuclear cells.88 Thus, in TNF or TNFRI-deficient mice granuloma formation is significantly delayed.89 In addition, TNFRI signalling is required for the modulation of the T-cell response because in TNFRI-deficient mice T-cell dependant granuloma decomposition is observed.90 Because LTα also engages the TNFRI and TNFRII receptor, LTα has a role similar to that of TNF as in the absence of LTα granulomas are not efficiently formed and T cells inappropriately activated do not enter into the lesions, resulting in premature death of infected mice.91 On the other hand, activation of the LTβR by heterotrimeric LTα1β2 is necessary for the full activation of the antibacterial defence mechanisms. Macrophages in LTβR-deficient mice show a gross delay in inducible nitric oxidase sythethase (iNOS) expression and rapidly succumb to M. tuberculosis infection. In contrast, LIGHT-deficient mice proofed to be equally resistant to M. tuberculosis infection as wild type mice.86

Since signalling of TNF and LTα are essential and non redundant prerequisites for immunity against Mycobacterium tuberculosis it is not surprising that treatment of patients with chronic inflammatory processes such as Crohn's disease (CD) rheumatoid arthritis (RA) and psoriasis with agents blocking TNF activity leads to an increased risk of reactivating tuberculosis.9296

Using TNFRII-deficient mice and bone marrow chimeras expressing TNFRII either on haematopoietic or non-haematopoietic cells demonstrated the requirement of TNFRII expression on vascular cells to induce TNF-mediated neurovascular lesions in experimental cerebral malaria.97,98

Treatment of mice infected with M. bovis bacillus Calmette—Guèrin (BCG) with a soluble inhibitor of LTβR activation (LTβR:Ig) interfered with granuloma formation by inhibiting macrophage activation and iNOS activity. Decreased IFN-γ and increased IL-4 production was also observed suggesting that the LTβR pathway is important in BCG infection in order to favour a Th1-type immune response.99 A recent report demonstrates that transgenic mice expressing a soluble form of HVEM (HVEM:Ig) showed marked resistance to herpes simplex-1 (HSV-1) infection when challenged intraperitoneally with HSV-1.100 The role of TNF/TNFR superfamily members in bacterial infections based on studies using gene targeted mice are summarized in Table 3.

Table 3
Role of TNF/TNFR superfamily members in bacterial infections based on studies using gene targeted mice

Inflammation

Very soon after the availability of purified TNF, it became evident that TNF has systemic endotoxic activity leading to fever, hypotension, and shock.101 Detailed investigations on the biological activities revealed that TNF is one of the most prominent inflammatory mediators and absolutely central in starting off the inflammatory reactions of the innate immune system including induction of cytokine production, activation and expression of adhesion molecules, and growth stimulation.102 The potent biological activity of TNF also explains the danger of tissue damage when TNF action is not carefully controlled.103

Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the intestinal tract. There is increasing evidence that the immune system plays a critical role in the development and perpetuation of ulcerative colitis (UC) and Crohn's disease (CD). The relevance of balanced cytokine levels has been established in colitis animal models.104 Results obtained by neutralization of TNF, IFN-γ or LTα1β2 in several colitis models demonstrated that these cytokines play a central role in experimental colitis.105,106 The LT pathway has been shown to be as important as the TNF system for disease development.107 In a dextran sulphate sodium (DSS)-induced colitis model inhibition of the LTβR signalling pathway using LTβR:Ig ameliorated the development and the histological manifestation of intestinal inflammation and results in the reduction of inflammatory cytokine expression such as TNF, IL-1 and IL-6. Furthermore a significant down-regulation of MAdCAM-1 expression in the intestinal epithelium was observed entailing reduced lymphocyte margination and extravasation into the inflammed mucosa.108

The first evidence that CD40/CD40L interactions are important in intestinal inflammation was demonstrated by the beneficial effect of CD40L antibodies in the murine model of hapten-induced colitis.109 Additional evidence in other models of experimental colitis, e.g. induced by transfer of CD45RBhigh CD4+ T cells into severe combined immunodeficiency (SCID) mice demonstrated that the development of colitis was paralleled by an increased expression of CD40 and its ligand on mRNA as well as on protein level. CD40L positive T cells induce the activation of monocytes and the production of proinflammatory cytokines. Activation of CD40 by CD40L positive T cells induces up-regulation of adhesion molecules and the production of chemokines by microvascular endothelial and mesenchymal cells, which very efficiently amplify the immune response in specific tissues and perpetuate mucosal inflammation.110 A phase I trial with antagonistic monoclonal antibody against CD40 is under way in CD patients and phase I and II trials with a humanized anti-CD40L antibody have been initiated.111 The results of these ongoing clinical trials will define the value of a biological therapy of blocking the CD40/CD40L pathway in IBD.

In vitro data suggested that the newly discovered TNF-superfamily cytokine TL1A could also be involved in initiating or promoting the Th1 response by enhancing IFN-γ production in UC and CD.112 Lamina propria T cells, especially CD4+ T cells constitutively express TL1A and a higher fraction of lamina propria mononuclear cells (LPMC) express the cognate receptor DR3 in UC and CD. IFN-γ production by PBMC and lamina propria lymphocytes (LPL) was dose-dependently augmented by using recombinant TL1A or by activation of its receptor DR3 with agonistic monoclonal antibody (mAb).112 The use of corresponding animal models should help to clarify whether TL1A and/or DR3 expression could possibly have a significant influence on mucosal inflammation in vivo.

Transgenic overexpression of LIGHT has been demonstrated to induce T-cell mediated intestinal inflammation in the RAG-1−/− transfer model accompanied by a dramatic increase in serum IgA levels similar to those in human IgA nephropathy (IgAN). LIGHT tg/LTβR−/− mice revealed that the engagement of LTβR by LIGHT is essential for both intestinal inflammation and hyperserum IgA syndrome in this animal model. These observations indicate a critical contribution of dysregulated LIGHT expression to intestinal inflammation and the pathogenesis to IgAN.113

Further evidence that the LT/LIGHT axis is as important as the TNF system for disease development has emerged in the murine collagen arthritis (CIA) model.

Prophylactic treatment with LTβR:Ig fusion protein blocked the induction of collagen-induced arthritis in mice and adjuvant arthritis in Lewis rats.114 Treatment of mice with established collagen induced arthritis reduced the severity of arthritic symptoms and joint tissue damage. Because treatment with LTβR:Ig ablated follicular dendritic cell (FDC) networks in the draining lymph nodes and impaired class switch and affinity maturation in the B-cell response these effects may account for the reduced pathological signs of disease. However, LTβR:Ig treatment did not affect passive immune complex triggered joint inflammation induced by a mixture of anticollagen mAb and endotoxin115 whereas anti-very late antigen-1 (VLA-1) mAb and TNFRI:Ig reduced disease symptoms in parallel experiments.116 This result indicates that inflammation triggered by immune complex deposition in the joints and endotoxin-induced monocyte/granulocyte activation does not involve the LT/LIGHT axis in this model of disease.

Further investigations targeting the B-cell response in CIA have demonstrated that the TNF-ligand superfamily member BAFF and the proliferation induced ligand APRIL together with their cognate receptor TACI play an important role in the humoral immune response in CIA. TACI:Ig blocks the activation of T cells in vitro and inhibits antigen-specific T-cell activation and priming in vivo. In the mouse model of CIA TACI:Ig treatment substantially inhibited inflammation, bone and cartilage destruction and disease development.117 Thus, BAFF and APRIL are important not only for B-cell function but also for T-cell mediated immune responses.

A role of osteoprotegerin and other member of the TNFR superfamily has been implicated by recent studies. Osteoprotegerin expressed by osteoblasts inhibits bone resorption and binds with high affinity to its ligand RANKL, thereby inhibiting RANKL from binding to its receptor RANK. RANKL-deficient mice exhibit both severe immunological abnormalities and osteoporosis. RANKL expressed by activated T cells induces osteoclastogenesis via a mechanism enhanced by cytokines, e.g. TNF and IL-1, that promote both inflammation and bone resorption. On the other hand this mechanism is inhibited by OPG, IL-4 and IL-10 which have anti-inflammatory effects and inhibit osteoclast formation. Thus bone erosion may result from activation of the RANK/RANKL system. Blocking this mechanism by OPG therapy might proof beneficial in rheumatoid inflammation.118

Gene-deficient mice lacking TNFRI and/or TNFRII proofed to be essential in dissecting the roles of these receptors in mediating and modulating inflammatory responses like in the pathogenesis of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalitis (EAE).30 While TNFRI and TNFRI and TNFRII double-deficient mice were completely resistant to clinical signs of disease paralleled by a specific Th1 cytokine production, TNFRII deficient mice exhibited exacerbated signs of EAE, enhanced Th1 cytokine production and an increased CD4+ T-cell infiltration in the central nervous system (CNS). Thus, TNFRI seems to be required for the initiation of the disease, whereas TNFRII may influence the regulation of the immune response.119

Furthermore, exacerbated endotoxin induced serum TNF levels and increased pulmonary inflammation in mice lacking TNFRII suggests a downmodulating role of TNFRII-mediated inflammatory responses.120

Sepsis

Despite advances in supportive care, sepsis and septic shock remain a major cause of mortality. Sepsis constitutes a systemic response to infection.121 This response is characterized by both pro-inflammatory and anti-inflammatory phases paralleled by the sequential expression of pro- and anti-inflammatory cytokines. TNF and IL-1 have been identified as the most important pro-inflammatory cytokines of the systemic inflammatory response as well as a major component in the pathogenesis of the septic shock syndrome. Their pro-inflammatory effects can be inhibited by soluble receptors/receptor-antagonists and anti-inflammatory cytokines such as IL-10 and transforming growth factor-βin vitro and in vivo.122125

Recent work has focused on modulating these responses in animal models. Several studies identified TNF as the prototype of a host damaging cytokine.126128 These results were supported by the observation that TNF injections lead to a septic like syndrome in mice.129 Infusion of anti-TNF antibodies in baboons protects from septic shock triggered by Escherichia coli infusion and LPS.130 In all these models TNFRI is essential in mediating TNF signalling since TNFRI-deficient mice are protected from LPS/D-GalN and Staphylococcus aureus superantigen/D-GalN-induced shock like syndromes.30 In other experimental models using concanvalin A (Con A) or Pseudomonas endotoxin A TNFRII signalling seems to be important for the host damaging effects.70,131 In accordance with clinical studies, animal models employing antagonists of host cytokines such as anti-TNF or TNFR:Ig decoy receptors and IL-1 receptor antagonist (IL-1Ra) could not provide conclusive evidence for an improved survival in sepsis. Further animal models of abdominal sepsis, e.g. cecal ligation and puncture (CLP) and colon ascendens stent peritonitis (CASP) both generating a septic focus and rapid invasion of gut bacteria into the blood stream and into solid organs have been put forward.132,133 CASP surgery employing TNFRI deficient mice revealed that the mortality rate does not differ when TNF signalling is mediated in the presence or absence of TNFRI; however, this model emphasized a beneficial role for IFN-γ in the survival of a polymicrobal sepsis.133 Studies employing the CLP model indicated that TNF is critically required for the survival in septic peritonitis.132 Furthermore, the interaction of endogenously produced TNF with TNFRII is needed for enhanced resistance to the bacterial challenge induced by CLP.134 In addition, after CLP a state of immunoparalysis characterized by a reduced capacity to produce TNF develops during which bacterial super-infections leads to increased lethality. Echtenacher and coworkers demonstrated in the CLP model that TNF substitution during the phase of immunoparalysis can be beneficial or deleterious, depending on the location of TNF activity, timing of TNF administration or the type of superinfection.135 From these results, the concept that TNF is solely host damaging has to be re-evaluated and future studies are required to analyse in more detail the molecular mechanisms in sepsis to define more targeted therapies.

Costimulatory signals from TNFR superfamily members

Several members of the TNFR superfamily are important for the effective generation of a T-cell response. These molecules control the absolute number of effector T cells during an immune response and are further responsible for the frequency of memory T-cell generation. Growing evidence has shown that Ox40, CD27, and HVEM regulate the expression and survival of CD4+ and CD8+ T cells when stimulated by their cognate ligands.136 Ox40 expression is induced on activated T cells at the peak of the primary immune response.137,138 Activated T cells expressing Ox40 have been identified at various sites in a number of inflammatory diseases such as EAE,139 the lamina propria of mice undergoing colitis and biopsies from patients with CD,140,141 joints of mice with experimentally induced RA.142 Ox40 ligand (Ox40L) is expressed on APCs such as DCs, B cells and macrophages. Interestingly Ox40L is also expressed on activated endothelial cells in vitro and in the colon of patients with CD implying a role in promoting the migration of Ox40 expressing T cells to distant inflammatory sites and subsequently providing costimulatory signals.143,144 Studies employing Ox40- or Ox40L-deficient mice demonstrated that CD4+ T-cell responses during viral infections were markedly reduced in these animals.145 Similarly, transgenic expression of Ox40L on DCs led to an increased number of CD4+ T cells146 while blocking the Ox40L dramatically reduced the number of T cells.147 Interestingly, Ox40 deficient T cells demonstrated a reduced proliferation rate and could not survive over a long period of time.138 These studies suggest that the Ox40/Ox40L interaction controls the number of effector T cells in a primary immune response and allow these cells to survive, proliferate and differentiate in a late immune response.

CD27 is expressed on resting CD4+ and CD8+ resting T cells and is strongly up-regulated upon stimulation.148 The ligand for CD27 (CD27L) is also inducible on professional APCs, similar to OX40 ligand, although is has been detected predominantly on B cells rather than on DCs. Furthermore CD27L has been found on activated T cells implying that CD27/CD27L may be involved in direct costimmulation between subsets of T cells as well as between T cells and APCs.149

CD27-deficient mice have been shown to be defective in both CD4+ and CD8+ T-cell responses to viruses and the generation of specific memory T cells.150 These data are supported by results obtained with mice transgenic for CD27L expressed on B cells. These mice had increased numbers of memory and effector T cells.151

Expression studies have demonstrated that HVEM mRNA and protein is constitutively expressed on peripheral T and B lymphocytes, monocytes and immature DCs.152,153 In contrast LIGHT gene expression is regulated in an inducible manner on lymphocytes, natural killer cells and also on immature DCs.64,152

Initial studies implied that HVEM is involved in T-cell coactivation. The addition of anti-HVEM antibodies to activated T cells led to reduced T-cell proliferation and cytokine production,154 whereas the addition of soluble LIGHT in a mixed lymphocyte reaction (MLR) enhanced T-cell proliferation.155 Additional studies have shown that LIGHT—HVEM signalling seems to play a costimulatory role in TCR-mediated T-cell proliferation.65,156 Transgenic expression of human or mouse LIGHT results in inflammatory phenotypes, and enhanced Th1 cytokine production especially in the intestine.157 Recently, in a cardiac allograft rejection model, LIGHT has been further implicated as a regulator of allogenic T-cell activation and graft rejection155 indicating that the LIGHT—HVEM axis is involved in costimulation between different subsets of T cells.

Another type of costimulatory signal involving the LIGHT/LTα1β2 and LTβR axis has been reported recently by demonstrating that bone marrow derived mast cells (BMMC) express the LTβR. Employing BMMCs derived from wildtype or LTβR-deficient mice Stopfer and coworkers demonstrated the expression of LTβR, but not of HVEM, on BMMCs at mRNA as well as at protein level.158 BMMCs were found to release cytokines like TNF, IL-4, IL-6 and chemokines (e.g. MIP-2 and RANTES) in a LTβR-specific manner upon stimulation with either recombinant LIGHT, agonistic anti-LTβR mAbs or activated T cells expressing the corresponding ligands. These data clearly show that LTβR expressed on mast cells can transduce a costimulatory signal in T-cell dependent mast cell activation.158

Autoimmunity

There is compelling evidence derived from recent animal studies and corresponding clinical trials that neutralization of TNF increases disease activity in T-cell dependent and independent autoimmune diseases.

Treatment of multiple sclerosis (MS) patients with anti-TNF mAb or soluble TNFR showed increased CNS lesions and disease activity.159161 In the mouse model of EAE, TNF-deficiency results in the exacerbation of the disease as well as the failure of repression of T-cell reactivity.162 In the murine model of lupus using the (NZB×NZW)F1 mouse model anti-TNF or heterozygous TNF-deficiency is paralleled by earlier disease onset and increased severity.163,164 Several lines of evidence suggest that TNF levels inversely affect T-cell responsiveness and TCR signalling.165 In contrast blockade of TNF activity in patients with RA by anti-TNF or soluble TNFR antagonists results in a dramatic decrease in disease activity and in some cases a complete remission although disease recurs after cessation of the therapy.166 Anti-TNF therapy in CD results in a dramatic decrease in symptoms in up to 80% of the patients.167

Treatment of psoriasis patients with anti-TNF leads to the clearing of skin lesions and a decrease in associated arthritis incidents.94 It has been suggested that in these autoimmune diseases in which TNF blockade is therapeutic (as mentioned above) the overproduction of TNF and related cytokines is part of the innate immune response and is expressed by monocytes and macrophages rather than by T cells.168 Recent studies presented evidence that the LTβR and its ligands (LTα/β and/or LIGHT) and the interaction of LIGHT with HVEM are important for the function of T cells in their interaction with other T cells, B cells and APCs, thus playing a critical role in the development and maintenance of a normal immune response and in the development of autoimmune disease.

Blockade of LTβR activation by administration of LTβR:Ig or by transgenic overexpression prevents the clinical signs of diabetes in non-obese diabetic (NOD) mice.169 Because binding of LIGHT to HVEM functions as a costimulatory receptor/ligand interaction and promotes T-cell proliferation as well as IFN-γ production soluble HVEM:Ig was used to interfere with LIGHT activation in vivo.156 These studies showed that HVEM:Ig was capable of down-regulating the T-cell response and furthermore was capable of significantly decreasing the development of diabetes in some NOD mice.170

Thus, it became clear that at least parts of the effects observed with LTβR:Ig are caused by the blockade of the LIGHT/HVEM interaction. A critical role for LTβ has further been implicated in the murine model of EAE.171 Furthermore, administration of LTβR:Ig ameliorated the signs of disease in experimental murine colitis models.106 A very recent report demonstrates that blocking LTβR activation diminishes inflammation via a reduced MAdCAM-1 expression and leucocyte margination in a murine model of chronic DSS-induced colitis.108

From these results it is clear that LTβR blockade will have multiple effects. It can thus be envisioned that the interference with LTβR activation (1) decreases the expression of adhesins and integrins, (2) interferes with the development of natural killer cells, dendritic APCs, and FDC formation, and (3) prevents a normal localization and interaction of T cells, B cells, and APCs.

A more detailed analysis of the mechanisms accompanied by the blockade of LTα/β and LIGHT on the function of T and B cells as well as their interaction with other cells types (e.g. FDCs and APCs) may lead to alternative methods for down-regulating the immune response in autoimmune diseases.

Because studies in patients with systemic lupus erythematosus (SLE) and Sjögren's syndrome revealed elevated BAFF serum levels correlating with elevated levels of autoreactive immunoglobulins, BAFF represents an appropriate target for intervention in autoimmune disease since elevated levels of autoantibodies contribute to disease pathology.172

BAFF and APRIL are members of the TNF superfamily that modulate B-cell activation, survival and development.173175 Transgenic overexpression of BAFF results in the expansion of mature B2 and B1 B cells in the spleen and in symptoms of autoimmune disease similar to SLE and Sjögren's syndrome. In BAFF-deficient mice B-cell development is blocked at the transitional B1 stage resulting in the deficiency of mature B cells paralleled by reduced IgM and IgG serum levels. Interestingly, thymocyte populations and peripheral CD3+ T-cell subpopulations seem not to be affected by BAFF-deficency.176

Both BAFF and APRIL bind to TACI which is expressed on B cells and activated T cells as well as to BCMA, which is only expressed on B cells. In vivo TACI:Ig can inhibit the level of circulating B220+ B cells, the production of antibodies to a T-cell dependent antigen and the spontaneous development of SLE.175,177 TACI:Ig treatment further inhibits both the production of collagen-specific antibodies and the progression of disease in a mouse model of RA. In addition to B cells, BAFF promoted T-cell activation possibly via increased cell survival mediated by BAFF receptor expressed on effector T cells.178 Therefore, the role of BAFF in autoimmune disease appears to be a combined effect of suppressed B-cell survival and perturbed T-cell activation.179

Recent studies have implicated CD30, originally identified as a cell surface antigen on Hodgkin and Reed—Steinberg cells in regulation of inflammatory responses.180,181 A recent report suggested CD30 as a possible candidate for a diabetes-susceptible gene (Idd9) in NOD mice.182 Administration of neutralizing anti-CD30 mAb completely suppressed the development of spontaneous diabetes in these mice. Additionally, the treatment with anti-CD30 ligand (CD30L) mAb also inhibited the development of diabetes induced by adoptive transfer of spleen cells from diabetic NOD mice into NOD—SCID mice. These results suggest that CD30/CD30L interaction plays important roles in both induction and effector phase of autoimmune diabetes in NOD mice.183

While CD30L is expressed on activated T-cells, neutrophils, eosinophils and resting B-cells the receptor is not only expressed on activated T- and B-cells but also on certain Treg cell populations.184 Previous results have demonstrated that TCR activation is required for Treg cells to become suppressive but that costimulatoy interactions by other members of the TNFR superfamily (e.g. Ox40/Ox40L, and 4-1BB/4-1BBL) are not critically involved.185 A recent study employing CD30-deficient mice and blocking anti-CD30L mAb demonstrated that CD30/CD30L interaction is critical for the ability of Treg cells to suppress allograft rejection and induce enhanced CD8+ T-cell apoptosis in an allograft rejection model.186 These results identified CD30/CD30L as molecules required for the regulation of memory T-cell responses that are involved in a variety of autoimmune disease pathogenesis.

Very recently it has been demonstrated that the glucocorticoid-induced TNF related protein (GITR), which is constitutively expressed on the surface of Treg cells, provides signals that abrogates Treg suppression. Removal of GITR expressing T cells or administration of anti-GITR mAb produced organ specific autoimmune disease.187 Further studies have shown evidence that CD4+ GITR+ T-cells regulate the mucosal immune response and intestinal inflammation. SCID mice restored with CD4+/GITR-deficient T cells developed wasting disease and severe colitis, while cotransfer of the CD4+/GITR+ T-cell population prevented the development of classical CD4+ CD45RBhigh T-cell transferred colitis. Additionally the administration of anti-GITR mAb induced chronic colitis in this model.188

Further evidence that GITR regulate the Treg responsiveness is given by the observation that anti GITR mAb treatment of SJL mice with EAE significantly exacerbated clinical disease severity, and CNS inflammation, paralleled by elevated levels of T-cell proliferation and cytokine production.189 Studies using a recombinant soluble form of GITR-ligand (GITRL) which is naturally expressed as a membrane bound form on the cell surface of APCs, such as dendritic cells, macrophages and B cells but not on T cells demonstrated that stimulation of GITR by GITRL abrogates Treg suppression by inducing NF-κB activation and subsequent IL-2 production.190 These findings demonstrate that GITR both turns off Treg cells and costimulates conventional T-cells. It is therefore tempting to speculate on the phenotype of GITR or GITRL transgenes or deficient-mice. Using these mice in several animal models will certainly give answers to the question whether deregulated expression of GITRL contributes to the development in autoimmune diseases. The role of TNF/TNFR superfamily members in models of autoimmune diseases based on studies using gene targeted mice are summarized in Table 4.

Table 4
Role of TNF/TNFR superfamily in autoimmunity based on studies using gene targeted mice

Conclusions

Collectively, the members of the TNF/TNFR superfamily play important roles in organogenesis and the maintenance of lymphoid microarchitecture (Table 1). Additionally, the receptor ligand interactions within this superfamily have been demonstrated to be essential in host defence mechanisms and the control of inflammatory processes. On the other hand, dysregulation of this family of cytokines results in a general paralysis of the immune response leading to the pathophysiological conditions of exacerbated and chronic inflammation and septic shock syndromes. Recent studies have established the members of this superfamily as mediators in autoimmune diseases such as rheumatoid arthritis, inflammatory bowel diseases, psoriasis and lupus-like syndromes. The future challenges will be translating the basis results that have been obtained from studies in animal models into the appropriate clinical therapy. The improvement of animal models will also be essential in order to gain more detailed insight into the complex regulation and diverse activities of the members of the TNF superfamily and their receptors.

During the preparation of this review HVEM has been identified as a unique ligand for the B and T lymphocyte attenuator (BTLA).191

Abbreviations

AITR
Activation induced TNF-receptor
BAFFR
B-cell activating factor receptor
BCMA
B-cell maturation antigen
BLC
B-lymphocyte chemoattractant
EDAR
Ectodysplasin (EDA) receptor
ELC
Epstein Barr virus-induced molecule 1 ligand chemokine
FDC
Follicular dendritic cells
HVEM
Herpes virus entry mediator
IKK
IkB-kinase
LIGHT
homologous to lymphotoxins exhibits inducible expression and competes with herpes simplex virus glycoprotein D for HVEM a receptor expressed on T cells
MOG
Myelin oligodendrocyte glycoprotein
OPG
Osteoprotegerin
RIP
Receptor interacting protein
SLC
Secondary lymphoid tissue chemokine
TACI
Transmembrane activator and CAML interactor
TRAIL-R1
TNF-related apoptosis inducing ligand receptor 1
TRAMP
TNF-like receptor apoptosis mediating protein
TROY
Member of the TNFR family
XEDAR
X-linked EDA-A2 receptor

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