Two routes to TNF-induced apoptosis

The cytokine tumour necrosis factor (TNF) exerts its many effects through two receptors: TNFR1, the main signalling receptor for the induction of cell death and gene regulation; and TNFR2, which signals cell proliferation, gene activation and apoptosis mainly in T cells. Despite intensive research, it is unclear whether TNFR1 and TNFR2 act cooperatively or have separate biological functions. Peter Vandenabeele and colleagues now report that, in the rat/mouse T cell hybridoma PC60, TNFR2 can generate an apoptotic cell death signal independently of TNFR1 (see p. 497). The authors engineered PC60 cells to express both human TNF receptors and then used mutants of human TNF capable of binding either human TNFR1 or human TNFR2 to investigate cell death induction in the T cell hybridoma. Among other results, they show that TNFR2-mediated apoptosis is blocked by caspase-8 inhibitors and depends on Fas-associated protein with death domain (FADD) but does not require simultaneous activation of TNFR1. Further work is now needed to reveal the signalling complexes that TNFR2 uses to induce apoptosis.