Members of the tumor necrosis factor receptor (TNFR) superfamily and their ligands are critical regulators of immune responses (1). They can be divided into two groups according to their intracellular structure and the types of signaling proteins that they activate. Death receptors (Fas, TNFR1, DR3, DR4, DR5, and DR6) contain a death domain through which they bind to adapter proteins such as TRADD (TNFR-associated death domain) or FADD (Fas-associated death domain)/MORT1, triggering apoptosis through recruitment and activation of caspase-8. Members of the other group (TNFR2, CD30, and CD40) lack a death domain. They bind TRAF (TNFR-associated factor) and activate c-Jun NH 2-terminal kinase (JNK) and the transcription factor Rel/NF-κB, thereby promoting cell survival, proliferation, and differentiation (1).

The functional distinction between these two groups is not absolute. Some receptors lacking death domains can trigger apoptosis by inducing the expression of membrane-anchored TNF ligand and by signaling through TNFR1 (2). Paradoxically, death receptors can also promote proliferation under certain circumstances. For example, TNFR1 is essential for liver regeneration after partial hepatectomy (3), and signaling through FADD is required for mitogen-induced T lymphocyte proliferation (4–6).