Human NKT cells mediate antitumor cytotoxicity directly by recognizing target cell CD1d with bound ligand or indirectly by producing IL-2 to activate NK cells

被引:283
作者
Metelitsa, LS
Naidenko, OV
Kant, A
Wu, HW
Loza, MJ
Perussia, B
Kronenberg, M
Seeger, RC
机构
[1] Childrens Hosp Los Angeles, Div Hematol Oncol, Dept Pediat, Los Angeles, CA 90027 USA
[2] Univ So Calif, Keck Sch Med, Los Angeles, CA 90027 USA
[3] La Jolla Inst Allergy & Immunol, Div Dev Immunol, San Diego, CA 92121 USA
[4] Thomas Jefferson Univ, Jefferson Med Coll, Kimmel Canc Ctr, Dept Microbiol & Immunol, Philadelphia, PA 19107 USA
关键词
D O I
10.4049/jimmunol.167.6.3114
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
alpha -Galactosylceramide (alpha 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/alpha GalCer tetrameric complexes were used to obtain highly purified human alpha 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 alpha 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 alpha GalCer. Upon human CD1d/alpha 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-gamma. 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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页码:3114 / 3122
页数:9
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