A subset of the tumour necrosis factor (TNF) receptor family contain a conserved intracellular motif, the death domain. Engagement of these receptors by their respective ligands initiates a signalling cascade that rapidly leads to cell death by apoptosis. We have cloned a new member of this family, TRICK2, the TRAIL (TNF-related apoptosis-inducing ligand) receptor inducer of cell killing 2. TRICK2 is expressed in a number of cell types, and to particularly high levels in lymphocytes and spleen. Two isoforms of the TRICK2 mRNA are generated by alternative pre-mRNA splicing and differ by a 29 amino-acid extension to the extracellular domain. Overexpression of TRICK2 rapidly induced apoptosis in 293T cells; this induction was dependent upon the presence of the death domain of TRICK2. Using a soluble molecule containing the TRICK2 extracellular domain, we demonstrated that TRICK2, like DR4 , is a receptor for TRAIL/APO-2L [2,3] and could inhibit TRAIL-induced killing of lymphocyte lines, such as the Jurkat T-cell line. TRAIL is upregulated upon lymphocyte activation, as is the intensively studied ligand for Fas, FasL . TRAIL and its receptors might therefore provide another system for the regulation of lymphocyte selection and proliferation, as well as providing an additional weapon in the armoury of cytotoxic lymphocytes.