Constitutive expression and role of the TNF family ligands in apoptotic killing of tumor cells by human NK cells

Natural killer cells mediate spontaneously secretory/necrotic killing again st rare leukemia cell lines and a nonsecretory/apoptotic killing against a large variety of tumor cell lines. The molecules involved in nonsecretory/a poptotic killing are largely undefined. In the present study, freshly isola ted, nonactivated, human NK cells were shown to express TNF, lymphotoxin (L T)-alpha, LT-beta, Fas ligand (L), CD27L, CD30L, OX40L, 4-1BBL, and TNF-rel ated apoptosis-inducing ligand (TRAIL), but not CD40L or nerve growth facto r. Complementary receptors were demonstrated to be expressed on the cell su rface of solid tumor cell lines susceptible to apoptotic killing mediated b y NK cells. Individually applied, antagonists of TNF, LT-alpha(1)beta(2), o r FasL fully inhibited NK cell-mediated apoptotic killing of tumor cells. O n the other hand, recombinant TNF, LT-alpha(1)beta(2), or FasL applied indi vidually or as pairs were not cytotoxic. In contrast, a mixture of the thre e ligands mediated significant apoptosis in tumor cells. These findings dem onstrate that human NK cells constitutively express several of the TNF fami ly ligands and induce apoptosis in tumor cells by simultaneous engagement o f at least three of these cytotoxic molecules.