Suicide by order: some open questions about the cell-killing activities of the TNF ligand and receptor families.

That leukocytes can produce proteins with cell-killing activities has been known for almost 30 years (Granger GA, Kolb EP. J Immunol 1968, 101; Ruddle NH, Waksman BH. J Exp Med 1968, 128, 1267-1279; Carswell EA, Old LJ, Kassel S, Green S, Fiore N, Williamson B. Proc Natl Acad Sci USA 1975, 72, 3666-3670). However, it is only recently that the nature of this cell killing activity has become clear. What appeared initially to be merely a toxic effect of the leukocyte-produced proteins (hence their initial name, 'lymphotoxins') has turned out to represent a new kind of biological mechanism, whose understanding required a radical change of concepts concerning the ways in which the life and death of the cell are controlled. The leukocyte-produced 'toxic' proteins turned out to act, not through any toxic feature of the proteins themselves, but by activating destructive mechanisms that pre-exist within the target cell. Their action thus represents a way by which one cell can dictate suicide to another. Within the last few years more has been learnt about their mechanisms of action than was learnt throughout the two preceding decades. Nevertheless, many questions still remain unresolved. The purpose of this exposition is to spell out some of these open questions.