A family of ligands for the TNF receptor superfamily

Abstract

Recent progress in the definition of molecules involved in immune regulation has led to the discovery of a number of type I membrane glycoproteins with a distinctive, cysteine-rich, repetitive domain structure within their extracellular regions. Because the prototype members of this family are receptors for cytokines (tumor necrosis factor [TNF] and nerve growth factor [NGF]), it was expected that the ligands for the other receptors would possess cytokine-like activities. This prediction has been fulfilled by the cloning of cDNA encoding a series of type II membrane glycoproteins, with homology to TNF, that bind to, and signal through, their cognate receptors. While the biological role of some of these ligand-receptor pairs remains obscure, at least two members of the family, CD40 and Fas, have proven their importance. The human X-linked immunodeficiency, hyper IgM syndrome, is the result of mutations in the CD40 ligand gene, and the Fas and Fas ligand genes are mutated in two mouse strains, lpr and gld, that develop autoimmune disease. These findings, together with other evidence, point to key roles of CD40/CD40 ligand interactions in immune activation, particularly in T-dependent B cell responses, and of Fas/Fas ligand in apoptosis and peripheral tolerance. These molecules, as well as the other ligands of the family, share the property of costimulation of T cell proliferation and are all expressed by activated T cells. More detailed analysis of the expression patterns of ligands and receptors on lymphocyte subpopulations will be necessary to define their different roles in immune activation and suppression.

Expression of TNF-related apoptosis-inducing Ligand receptors and antitumor tumor effects of TNF-related apoptosis-inducing Ligand in human hepatocellular carcinoma

“…Maladjustment or disturbance in apoptotic process will result in transformation and provide a growth advantage to transformed cells. Members of the tumor necrosis factor (TNF) superfamily contribute to a variety of cell biological functions, including cellular activation, proliferation and death, by interaction with their corresponding receptors [1][2][3] . TNF and fasL have been focused on because of they can induce tumor cells apoptosis, whereas TNF and fas ligand were unlikely to provide useful target neoplastic elimination of tumors cells for two reasons.…”

Differential Regulation of the Expression of CD95 Ligand, Receptor Activator of Nuclear Factor-κB Ligand (RANKL), TNF-Related Apoptosis-Inducing Ligand (TRAIL), and TNF-α During T Cell Activation

“…Several family members have been identified in mammalian cells. Each member of the TNFR family binds to its distinct cognate ligand(s) (1,2). The identification of this family of proteins is based on the shared homologies in their cysteine-rich extracellular ligand-binding domains and intracellular effector (death) domains (3).…”

Expression, purification and crystallization of recombinant human TRAIL

“…However, further model building and re®nement were hampered by low sequence homology (19% sequence homology between TNF-and TRAIL) and a high loop-structure content (46% in the structure of TNF-). Some loop regions of TNF family cytokines have been known to interact directly with their receptors (Van Ostade et al, 1991, 1994Banner et al, 1993;Cha et al, 1998). Residues 129± 161, 215±218 and 264±274 of TRAIL are especially likely to interact with receptors, as the corresponding loops of TNFhave been revealed to interact with its receptor in the structure of TNF-in complex with TNF-R1.…”

“…Nine members of the TNF family are known: TNF-, TNF-(known as lymphotoxin or LT-), lymphotoxin-(LT-), 41BBL, OX40L, CD27L, CD30L, CD40L and FasL (also known as Apo-1L) (Cosman, 1994). With the exception of LT-, all these ligands are type II membrane proteins which are processed proteolytically to form a soluble homotrimeric structure, as suggested by the structures of the mature proteins TNF- (Eck & Sprang, 1989;Jones et al, 1989), TNF- (Eck et al, 1992) and CD40L (Karpusas et al, 1995).…”