Natural killer (NK) cell-mediated cytotoxicity: Differential use of TRAIL and Fas ligand by immature and mature primary human NK cells

Mature natural killer (NK) cells use Ca2+-dependent granule exocytosis and release of cytotoxic proteins, Fas ligand (FasL), and membrane-bound or sec reted cytokines (tumor necrosis factor [TNF]-alpha)to induce target cell de ath. Fas belongs to the TNF: receptor family of molecules, containing a con served intracytoplasmic "death domain" that indirectly activates the caspas e enzymatic cascade and ultimately apoptotic mechanisms in numerous cell ty pes. Two additional members of this family, DR4 and DR5, transduce apoptoti c signals upon binding soluble TNF-related apoptosis-inducing ligand (TRAIL ) that, like FasL, belongs to the growing TNF family of molecules. Here, we report th:lt TRAIL produced or expressed hy different populations of prima ry human NK cells is functional, and represents a marker of differentiation or activation of these, and possibly other, cytotoxic leukocytes. During d ifferentiation NK cells, sequentially and differentially, use distinct memb ers of the TNF family or granule exocytosis to mediate target cell death. P henotypically immature CD161(+)/CD56(-) NK cells mediate TRAIL-dependent bu t not FasL- or granule release-dependent cytotoxicity, whereas mature CD56( +) NK cells mediate thr latter two.