Comment

It seems that wherever one turns in mammalian biology, from conception through normal development to death, cytokines of immunological interest have become inserted as important regulators of tissue activity. Or have they? The truth is that at various stages the evolving immune system has borrowed widely to turn existing regulatory and effector molecules to new advantages.

The tumour necrosis factor (TNF) and TNF receptor (TNFR) families

The TNF and TNFR families of molecules1-3 consist of the ligands TNF, lymphotoxins alpha and beta (LT-α, LT-β), nerve growth factor (NGF), Fas ligand (FasL), CD27 ligand, CD30 ligand, CD40 ligand, OX40 (CD134) ligand, and 4–1BB ligand and their receptors (which, in most cases, are ligand specific). Of the ligands, TNF, LT-α and NGF are secreted products, which in each ease associate to form biologically active homotrimers (LT-α₃ in the case of LT-α). Both TNF and LT-α₃ are approximately equally favoured ligands for two receptors, TNFR I (55 kD) and TNFR II (75 kD). LT-β is a membrane protein that is not secreted and has not been observed as a homotrimer. Expression of LT-β on the cell surface seems to require co-expression of LT-α and their association in the heterotrimers LT-α₂β₁ (minority) or LT-α₁β₂ (majority). LT-α₂β₁ may signal via either of the TNF receptors but LT-α₁β₂ signals via a specific receptor (LTβ-R; also known as TNFR related protein, TNFR_rp).

The TNF ligand family are, in general, inducers of either cell proliferation or cell death and the receptors for some are expressed by a wide range of tissues. It would not, therefore, have been surprising if loss of function in ligand/receptor pairs in this family by natural mutations or through gene targeting had caused significant defects in general embryonic morphogenesis. In fact, this has not been the case, even when …