NKT cells act as regulatory cells rather than killer cells during activation of NK cell-mediated cytotoxicity by alpha-galactosylceramide in vivo.

Administration of NKT cell ligands, alpha-galactosylceramide (alpha-GalCer) resulted in the activation of both cytokine production and natural killing. These responses were abolished in both CD1d-deficient mice and Valpha14NKT-deficient mice. Therefore, NKT cells have been considered to be responsible cells for both cytokine production and natural killing. Here, we reevaluated a critical role of NKT and NK cells at early time after alpha-GalCer administration. Intracellular staining experiments demonstrated that NKT cells were the earliest source of both IL-4 and IFN-gamma production after alpha-GalCer administration in vivo. However, these alpha-GalCer-activated NKT cells exhibited no significant natural killing activity. In contrast, isolated NK1.1+CD3- classical NK cells exhibited greatly enhanced natural killing activity 6 h after alpha-GalCer administration. NKT cells, however, exhibited a strong cytotoxicity when they were activated and expanded with alpha-GalCer plus IL-2 in vitro. These results indicated that NKT cells act as regulatory cells via production of cytokines for activation of NK cell-mediated cytotoxicity in vivo at early phase after alpha-GalCer administration. Thus, NK cells rather than NKT cells may be a crucial early activated killer induced by alpha-GalCer in vivo.