The continuously growing family of structurally related proteins of the tumor necrosis factor (TNF) family has received enormous scientific attention due to their important role in the regulation of cell activation, survival, death and many other physiological and pathophysiological events (reviewed in Locksley et al.1). In this News and Commentary, we will focus on the only recently recognized and appreciated role of TNF-related apoptosis-inducing ligand (TRAIL) in regulating various physiological and pathophysiological processes involving immune cells.

There is accumulating evidence that TRAIL-induced apoptosis is not limited to transformed cells, but may also be induced in primary cells. It is likely that this observation has been missed previously since TRAIL sensitivity in primary cells may be under stringent control and only be activated under certain circumstances. For example, primary mouse plasma cells generated in a T-cell-dependent immune response become sensitive to TRAIL-induced apoptosis. By contrast, resting and activated B cells are resistant to TRAIL-mediated killing despite comparable expression of TRAIL receptors.2 The selective sensitivity of plasma cells correlates with decreased expression of CD40 and reduced activation of NFκB, thus leading most likely to lower levels of antiapoptotic molecules. The in vivo relevance of this TRAIL-based elimination of plasma cells is uncertain, since no accumulation of plasma cells has been observed so far in the absence of TRAIL, although neutralization of TRAIL in vivo leads to increased antibody production.3 The observation proves, however, that depending on the activation and differentiation status also primary cells can undergo TRAIL-induced apoptosis.

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