Tetsu Kawano

TL;DR: Glycosylceramide-mediated proliferative responses of Valpha14 NKT cells were abrogated by treatment with chloroquine-concanamycin A or by monoclonal antibodies against CD1d/Vbeta8, CD40/CD40L, or B7/CTLA-4/CD28, but not by interference with the function of a transporter-associated protein.

TL;DR: The Vα14 NKT cell–deficient mice could no longer mediate the interleukin-12 (IL-12)–induced rejection of tumors, and they mediated their cytotoxicity by an NK-like effector mechanism after activation with IL-12.

TL;DR: T cell receptor Jα281 gene-targeted mice confirmed a critical function for NKT cells in protection from spontaneous tumors initiated by the chemical carcinogen, methylcholanthrene, which is the first description of an antitumor function in the absence of exogenously administered potent stimulators such as IL-12 or α-galactosylceramide.

Abstract: The natural killer T (NKT) cell ligand α-galactosylceramide (α-GalCer) exhibits profound antitumor activities in vivo that resemble interleukin (IL)-12–mediated antitumor activities. Because of these similarities between the activities of α-GalCer and IL-12, we investigated the involvement of IL-12 in the activation of NKT cells by α-GalCer. We first established, using purified subsets of various lymphocyte populations, that α-GalCer selectively activates NKT cells for production of interferon (IFN)-γ. Production of IFN-γ by NKT cells in response to α-GalCer required IL-12 produced by dendritic cells (DCs) and direct contact between NKT cells and DCs through CD40/CD40 ligand interactions. Moreover, α-GalCer strongly induced the expression of IL-12 receptor on NKT cells from wild-type but not CD1−/− or Vα14−/− mice. This effect of α-GalCer required the production of IFN-γ by NKT cells and production of IL-12 by DCs. Finally, we showed that treatment of mice with suboptimal doses of α-GalCer together with suboptimal doses of IL-12 resulted in strongly enhanced natural killing activity and IFN-γ production. Collectively, these findings indicate an important role for DC-produced IL-12 in the activation of NKT cells by α-GalCer and suggest that NKT cells may be able to condition DCs for subsequent immune responses. Our results also suggest a novel approach for immunotherapy of cancer.

TL;DR: The results suggest that the ligand-activated Valpha14 NKT cells kill tumor cells directly through a CD1d/Valpha14 T cell receptor-independent, NK-like mechanism.