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,
,
Departments of
*
Pathology and
Medicine, and
University of Pittsburgh School of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213
Natural killer cells mediate spontaneously secretory/necrotic
killing against rare leukemia cell lines and a nonsecretory/apoptotic
killing against a large variety of tumor cell lines. The molecules
involved in nonsecretory/apoptotic killing are largely undefined. In
the present study, freshly isolated, nonactivated, human NK cells were
shown to express TNF, lymphotoxin (LT)-
, LT-ß, Fas ligand (L),
CD27L, CD30L, OX40L, 4-1BBL, and TNF-related apoptosis-inducing ligand
(TRAIL), but not CD40L or nerve growth factor. Complementary receptors
were demonstrated to be expressed on the cell surface of solid tumor
cell lines susceptible to apoptotic killing mediated by NK cells.
Individually applied, antagonists of TNF,
LT-1ß2, or FasL fully inhibited NK
cell-mediated apoptotic killing of tumor cells. On the other hand,
recombinant TNF, LT-1ß2, or FasL applied
individually or as pairs were not cytotoxic. In contrast, a mixture of
the three ligands mediated significant apoptosis in tumor cells. These
findings demonstrate that human NK cells constitutively express several
of the TNF family ligands and induce apoptosis in tumor cells by
simultaneous engagement of at least three of these cytotoxic
molecules.
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