Dendritic cell-mediated NK cell activation is controlled by Jagged2–Notch interaction

Departments of *Immunology and Parasitology and
^†Digestive and Pediatric Surgery, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima 770-8503, Japan;
^‡Division of Cell Biology, Bio-medical Research Center, and
^§Department of Immunology, Juntendo University School of Medicine, Tokyo 113-8421, Japan; and
^¶Department of Cell Therapy and Transplantation Medicine, University of Tokyo Hospital, 7-3-1 Hongo, Tokyo 113-8421, Japan

Edited by Tak Wah Mak, University of Toronto, Toronto, ON, Canada, and approved February 29, 2008 (received for review October 18, 2007)

Abstract

Natural killer (NK) cells regulate various immune responses by exerting cytotoxic activity or secreting cytokines. The interaction of NK cells with dendritic cells (DC) contributes to NK cell-mediated antitumor or antimicrobial responses. However, the cellular and molecular mechanisms for controlling this interaction are largely unknown. Here, we show an involvement of Jagged2–Notch interaction in augmenting NK cell cytotoxicity mediated by DC. Enforced expression of Jagged2 on A20 cells (Jag2-A20 cells) suppressed their growth in vivo, which was abrogated by depleting NK cells. Moreover, Jag2-A20 cells exerted a suppression on the growth of nonmanipulated A20 cells in SCID mice in an NK-dependent manner. Consistently, coinoculation of A20 cells with DC overexpressing Jagged2 (Jag2-DC) suppressed the growth of A20 cells in mice. Stimulation of NK cells with Jagged2 directly enhanced their cytotoxicity, IFN-γ production, and proliferation. Ligation of Notch2 on NK cells enhanced their cytotoxic activity, and Jag2-DC or CpG-treated DC-mediated NK cell cytotoxicity was suppressed by a γ-secretase inhibitor. These results indicate that the Jagged2–Notch axis plays a crucial role in DC-mediated NK cell cytotoxicity. Furthermore, manipulation of this interaction may provide an approach to induce potent tumor immunity or to inhibit certain autoimmune diseases caused by NK cell activation.

Footnotes

^‖To whom correspondence should be addressed at:
Department of Immunology and Parasitology, Institute of Health Biosciences, University of Tokushima Gradate School, 3-18-15 Kuramoto, Tokushima 770-8503, Japan.
E-mail: yasutomo{at}basic.med.tokushima-u.ac.jp
Author contributions: M.K. and T.Y. contributed equally to this work; M.S. and K.Y. designed research; M.K., T.Y., Y.M., and A.K. performed research; C.I., Y.M., A.K., H.Y., and S.C. contributed new reagents/analytic tools; M.K., T.Y., Y.M., A.K., H.Y., and K.K. analyzed data; and K.Y. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0709919105/DCSupplemental.