The TNF receptor superfamily of cellular and viral proteins: Activation, costimulation, and death

Tumor necrosis factor (TNF) seems always to have enjoyed a rather conspicuous visibility in biomedical research. With historical roots in the century-old phenomenon of bacterial-induced hemorrhagic necrosis of tumors, TNF - or, rather, its two homologous forms, TNF alpha and LT alpha (lymphotoxin TNF beta ) - were finally molecularly cloned in 1984, among the very first cytokines to be so unambiguously defined. Although TNF alpha and LT alpha , classically the respective products of activated macrophages and T cells, can indeed kill many transformed lines, these functionally similar and extraordinarily pleiotropic cytokines are today viewed as primary mediators of immune regulation and the inflammatory response, closely linked to the development of disease. The crucial involvement of TNF, for example, in septic shock, some autoimmune disorders, and graft-host disease is well established. The distinctive but overlapping cellular responses their interactions produce clearly define developmental and regulatory networks involving cells of the lymphoid, hematopoetic, and other lineages. In this minireview we make no attempt to discuss individual members comprehensively and instead highlight emerging global characteristics that distinguish them from other cytokine families: structure, biological networks, and the intriguing ability of some members to induce cell death. A new face to the TNF system seems at hand.