Structural and biological features of the TNF receptor and TNF ligand superfamilies: Interactive signals in the pathobiology of Hodgkin's disease

Members of the TNF receptor superfamily are type I membrane glycoproteins with limited homology (overall homologies: 25%–30%) in the extracellular domain containing variable numbers of cysteine-rich repeats. In contrast, the TNF ligand superfamily members (with the exception of LT-a) are type II membrane glycoproteins with limited homology to TNF (overall homologies: 20%) in the extracellular region. TNF and LT-α are trimeric proteins and are composed of n-strands forming ß-jellyroll. the homology of the ß-strand regions for the TNF ligand superfaniily members suggests a similar trimeric or multimeric complex formation for the other members. A genetic linkage, as evidence for evolutionary relatedness, is also found by chromosomal cluster for CD30, CD120b, 4-1BB and OX40 to 1p36; CD27, CD120a and TNFR-RP to 12p13; TNF, LT-a and LT-ß to 6p2l; CD27L and 4-1BBL to 19p13; CD95L and OX40L to 1q25. TNF, LT-a and LT-ß and their receptors (CD120a, CD120b, TNFR-RP) interact in a complex fashion. Other family members, however, show a one ligand/one receptor binding principle. Signals can also be transduced through at least some of the ligands. TNF superfamily ligands are involved in induction of cytokine secretion, upregulation of adhesion molecules, activation antigens and costimulatory proteins, all known to amplify stimulatory and regulatory signals that occur during immune responses. On the other hand, differences in the distribution, kinetics of induction and requirements for induction support the view of a defined role for each of the ligands for T-cell-mediated immune activities. The shedding of members of the TNF receptor superfamily could limit the signals mediated by the corresponding ligands, as a functional regulatory mechanism. Induction of cytotoxic cell death is another common functional feature of this cytokine family (TNF, LT-α, CD30L, CD95L and 4-1BBL). Further studies have to identify unique versus redundant biological and physiological functions for each of the TNF superfamily ligands. In addition to other cytokines primary H-RS cell frequently express at least TNT, LT-α, CD27L and CD30L, but not CD40L. Furthermore, H-RS cells express several TNT receptors, such as CD30, CD40, CD95, CD120a, CD120b and 4-1BB. The TNF-like ligands might support growth and activation of HD-associated tumor cells and/or interact with surrounding reactive bystander cells, particularly T-cells. The different interactions between H-RS cells and surrounding reactive bysta