role in sepsis and that it is indeed required to control a sublethal sepsis, as they elegantly showed in relevant mouse models of sepsis that do not solely rely on the injection of lipopolysaccharide (LPS) (Echtenacher et al., 1995). This setback almost led to a halt of the attempts to take the inhibition of TNF forward clinically. However, when Mark Feldmann and colleagues in London, United Kingdom, then showed that inhibition of TNF interfered with collagen-induced arthritis, a model for the common human disease rheumatoid arthritis (RA), the field was suddenly revived (Williams et al., 1992). The subsequent clinical trials with RA patients returned excellent results and were successfully concluded a few years later. In the meantime, virtually millions of RA patients have benefitted from therapy with TNF blockers, which have revolutionized the treatment of this disease. Other inflammatory diseases such as Crohn’s disease and psoriasis, among many others, can be treated with TNF blockers, and success rates are often higher than 50%. The development of biotherapeutic TNF blockers is one of the biggest success stories in recent biomedical research. Hence the investigation of the biology of TNF receptorligand superfamilies has already created a huge impact on human health. Further success along these lines is eagerly awaited.

3.2. The DR3 system

On the basis of the presence of the DD and its high sequence homology with TNF-R1, in 1996 several groups discovered a third DD-containing receptor. The different groups came up with a number of different names for this receptor, but only two of these names are still used: DR3 and TNF receptor apoptosis-mediating protein (TRAMP). DR3 has been shown to bind to the TNFlike protein 1A (TL1A), an endothelial cell-derived factor. As in the case of TNF-R1, ligand-induced cross-linking of DR3 primarily activates NF-kB and MAP kinase signaling and only secondarily induces apoptosis. The homology of the TL1A/DR3 and the TNF/TNF-R1 systems is so substantial that this system has even been referred to as the TNF system of the gut at the most recent TNF conference. This also has to do with the fact that DR3 is mainly expressed in lymphoid cells of the gut-associated lymphoid tissue (GALT), yet it is also found on cells in other lymphoid organs, including the thymus and spleen. DR3 is constitutively expressed by conventional T cells and natural killer cells. In T cells, its expression is strongly upregulated after activation.

Thus far, TL1A has only been shown to induce apoptosis after addition of cycloheximide. However, in primary T cells, TL1A has been reported to enhance

proliferation and production of IL-2 and interferon gamma induced by T-cell receptor cross-linking. The expression of TL1A is inducible in professional APCs (e.g., dendritic cells, macrophages, and B cells) and T cells, but it can also be expressed by nonimmune cells, such as smooth muscle cells and endothelial cells, during conditions of inflammation.

Less is known about DR3 signaling, but it has been suggested to interact with TRADD and FADD. However, given its high similarity with TNF-R1, it is quite likely that the early data on DR3 signaling, which were at least in part over-expression–based analyses, may have been somewhat misleading. It is quite likely that DR3 mediates gene induction in a manner similar to that of TNFR1. However, these mechanisms are far less established for DR3 than for TNF-R1. Indeed, although DR3 was initially named death receptor 3 because of its intracellular DD, more recent functional data suggest that the activity of DR3 is mainly proinflammatory. DR3 is a strong activator of NF-κB, and DR3 signaling can result in the increased accumulation of T cells and resistance to apoptosis. It is important to note that DR3 has been associated with the pathogenesis of RA. This is supported by the fact that DR3-deficient mice are more resistant to collagen-induced arthritis. In line with these results, activation of DR3 by TL1A exacerbated arthritis in a doseand DR3-dependent manner. Because it was shown that treatment with TL1A-blocking antibodies protected animals from collagen-induced arthritis, targeting the DR3/TL1A pathway may represent a novel anti-inflammatory therapeutic approach for RA patients who do not respond to therapy with TNF blockers or become refractory to it. Moreover, genetic variants of TL1A and DR3 have also been associated with Crohn’s disease.

Reports have also shown that DR3 is essential for other, T-cell–mediated inflammatory diseases. Using DR3-deficient mice, studies have shown that DR3 is required for TL1A-induced T-cell costimulation and that dendritic cells are the likely source of TL1A. DR3 expression on T cells has been found to be required for immunopathology, local T-cell accumulation, and cytokine production in experimental autoimmune encephalomyelitis and allergic lung inflammation, two disease models that depend on distinct effector T-cell subsets. In the development of allergic lung inflammation, which leads to asthma, DR3 is the essential trigger for IL-13 release by natural killer T cells and for amplification of the Th2 response by Th2-polarized CD4 cells. In vivo blockade of TL1A inhibits lung inflammation and production of Th2 cytokines. Accordingly, blockade of DR3 by a dominant-negative transgene