Murine Vα14 natural killer T (NKT) cells are thought to play a crucial role in various immune responses, including infectious, allergic, and autoimmune diseases. Because Vα14 NKT cells produce large amounts of both interleukin (IL)-4 and interferon (IFN)-γ upon in vivo stimulation with a specific ligand, α-galactosylceramide (α-GalCer), or after treatment with anti-CD3 antibody, a regulatory role on helper T (Th) cell differentiation has been proposed for these cells. However, the identity of the cytokine produced by Vα14 NKT cells that play a dominant role on the Th cell differentiation still remains controversial. Here, we demonstrate by using Vα14 NKT-deficient mice that Vα14 NKT cells are dispensable for the induction of antigen-specific immunoglobulin (Ig)E responses induced by ovalbumin immunization or Nippostrongylus brasiliensis infection. However, upon in vivo activation with α-GalCer, Vα14 NKT cells are found to suppress antigen-specific IgE production. The suppression appeared to be IgE specific, and was not detected in either Vα14 NKT– or IFN-γ–deficient mice. Consistent with these results, we also found that ligand-activated Vα14 NKT cells inhibited Th2 cell differentiation in an in vitro induction culture system. Thus, it is likely that activated Vα14 NKT cells exert a potent inhibitory effect on Th2 cell differentiation and subsequent IgE production by producing a large amount of IFN-γ. In marked contrast, our studies have revealed that IL-4 produced by Vα14 NKT cells has only a minor effect on Th2 cell differentiation.

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A unique lymphocyte lineage, the Vα14 NKT cells, expresses both NK1.1 and an invariant antigen receptor encoded by Vα14 and Jα281 gene segments. Vα14 NKT cells play crucial roles in various immune responses, including autoimmune diseases, allergic reactions and anti‐tumor immunity. Vα14 NKT cells were demonstrated to be essential for anti‐tumor effect of IL‐12 in vivo. Here, we report that adoptive transfer of IL‐12‐activated Vα14 NKT cells prevents hepatic metastasis of B16 melanoma. The injection of large amounts of IL‐2, IL‐4, and IFN‐γ, which are cytokines produced by activated Vα14 NKT cells, exhibited no significant inhibition of the metastasis of this melanoma. The cells prepared from the liver of IL‐12‐injected mice expressed a potent cytotoxic activity on B16 melanoma cells in vitro. Although the adoptive transfer of IL‐12‐activated Vα14 NKT cells prevents hepatic metastasis of B16 melanoma, activated NK cells from IL‐12‐injected RAG‐1−/− mice failed to inhibit the metastasis of this melanoma. Thus, the anti‐tumor effect of IL‐12 can be replaced by adoptive transfer of IL‐12‐activated Vα14 NKT cells but not by IL‐12‐activated NK cells, suggesting a minor role of NK cells for the IL‐12‐mediated anti‐tumor effect in this experimental system. Moreover, our studies have suggested the involvement of direct cytotoxic mechanisms rather than cytokine‐mediated immune responses at the effector phase of the Vα14 NKT cell‐mediated anti‐tumor activity. © 2001 Wiley‐Liss, Inc.