NKT cells demonstrate antitumor activity when activated to produce Th1 cytokines by DCs loaded with α-galactosylceramide, the prototypic NKT cell–activating glycolipid antigen. However, most patients do not have sufficient numbers of NKT cells to induce an effective immune response in this context, indicating a need for a source of NKT cells that could be used to supplement the endogenous cell population. Induced pluripotent stem cells (iPSCs) hold tremendous potential for cell-replacement therapy, but whether it is possible to generate functionally competent NKT cells from iPSCs has not been rigorously assessed. In this study, we successfully derived iPSCs both from embryonic fibroblasts from mice harboring functional NKT cell–specific rearranged T cell receptor loci in the germline and from splenic NKT cells from WT adult mice. These iPSCs could be differentiated into NKT cells in vitro and secreted large amounts of the Th1 cytokine IFN-γ. Importantly, iPSC-derived NKT cells recapitulated the known adjuvant effects of natural NKT cells and suppressed tumor growth in vivo. These studies demonstrate the feasibility of expanding functionally competent NKT cells via an iPSC phase, an approach that may be adapted for NKT cell–targeted therapy in humans.
Hiroshi Watarai, Shin-ichiro Fujii, Daisuke Yamada, Andrei Rybouchkin, Sakura Sakata, Yuko Nagata, Midori Iida-Kobayashi, Etsuko Sekine-Kondo, Kanako Shimizu, Yohei Shozaki, Jafar Sharif, Masashi Matsuda, Shinobu Mochiduki, Takanori Hasegawa, Genta Kitahara, Takaho A. Endo, Tetsuro Toyoda, Osamu Ohara, Ken-ichi Harigaya, Haruhiko Koseki, Masaru Taniguchi
Generation of iPSCs harboring NKT cell–specific rearranged T cell receptor loci.