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
Open Access
- 15 September 2001
- journal article
- Published by The American Association of Immunologists in The Journal of Immunology
- Vol. 167 (6), 3114-3122
- https://doi.org/10.4049/jimmunol.167.6.3114
Abstract
α-Galactosylceramide (αGalCer) 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/αGalCer tetrameric complexes were used to obtain highly purified human αGalCer-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 αGalCer. 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 αGalCer. Upon human CD1d/αGalCer 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-γ. 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.Keywords
This publication has 58 references indexed in Scilit:
- TRAIL expression by activated human CD4+Valpha24NKT cells induces in vitro and in vivo apoptosis of human acute myeloid leukemia cellsBlood, 2001
- Selective induction of NK cell proliferation and cytotoxicity by activated NKT cellsEuropean Journal of Immunology, 2000
- THE CD1 SYSTEM: Antigen-Presenting Molecules for T Cell Recognition of Lipids and GlycolipidsAnnual Review of Immunology, 1999
- CD161 (NKR-P1A) Costimulation of CD1d-dependent Activation of Human T Cells Expressing Invariant Vα24JαQ T Cell Receptor α ChainsThe Journal of Experimental Medicine, 1998
- Requirement for V α 14 NKT Cells in IL-12-Mediated Rejection of TumorsScience, 1997
- Multiply attenuated lentiviral vector achieves efficient gene delivery in vivoNature Biotechnology, 1997
- MOUSE CD1-SPECIFIC NK1 T CELLS: Development, Specificity, and FunctionAnnual Review of Immunology, 1997
- In Vivo Gene Delivery and Stable Transduction of Nondividing Cells by a Lentiviral VectorScience, 1996
- Trafficking and activation of murine natural killer cells: Differing roles for IFN-γ and IL-2Cellular Immunology, 1990
- Characterization of a monoclonal anti‐β2‐microglobulin antibody and its use in the genetic and biochemical analysis of major histocompatibility antigensEuropean Journal of Immunology, 1979