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*
Division of Hematology-Oncology, Department of Pediatrics, Children’s Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, CA 90027;
Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121; and
Kimmel Cancer Center, Department of Microbiology and Immunology, Jefferson Medical College, Philadelphia, PA 19107
-Galactosylceramide (GalCer) stimulates NKT cells and has
antitumor activity in mice. Murine NKT cells may directly kill tumor
cells and induce NK cell cytotoxicity, but the mechanisms are not well
defined. Newly developed human CD1d/GalCer tetrameric complexes were
used to obtain highly purified human GalCer-reactive NKT cell lines
(>99%), and the mechanisms of NKT cell cytotoxicity and activation of
NK cells were investigated. Human NKT cells were cytotoxic against
CD1d- neuroblastoma cells only when they were rendered
CD1d+ by transfection and pulsed with GalCer. Four other
CD1d- tumor cell lines of diverse origin were resistant to
NKT cells, whereas Jurkat and U937 leukemia cell lines, which are
constitutively CD1d+, were killed. Killing of the latter
was greatly augmented in the presence of GalCer. Upon human
CD1d/GalCer recognition, NKT cells induced potent cytotoxicity of NK
cells against CD1d- neuroblastoma cell lines that were not
killed directly by NKT cells. NK cell activation depended upon NKT cell
production of IL-2, and was enhanced by secretion of IFN-
. These
data demonstrate that cytotoxicity of human NKT cells can be CD1d and
ligand dependent, and that TCR-stimulated NKT cells produce IL-2 that
is required to induce NK cell cytotoxicity. Thus, NKT cells can mediate
potent antitumor activity both directly by targeting CD1d and
indirectly by activating NK cells.
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