Inhibition of T helper cell type 2 cell differentiation and immunoglobulin E response by ligand-activated Vα14 natural killer T cells

Murine V alpha 14 natural killer T (NKT) cells are thought to play a crucial role in various immune responses, including infectious, allergic, and autoimmune diseases. Because V alpha 14 NKT cells produce large amounts of both interleukin (IL)-4 and interferon (IFN)-gamma upon in vivo stimulation with a specific ligand, alpha-galactosylceramide (alpha-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 V alpha 14 NKT cells that play a dominant role on the Th cell differentiation still remains controversial. Here, we demonstrate by using V alpha 14 NKT-deficient mice that V alpha 14 NKT cells are dispensable for the induction of antigen-specific immunoglobulin (Ig)E responses induced by ovalbumin immunization or Nipostrongylus brasiliensis infection. However, upon in vivo activation with alpha-GalCer, V alpha 14 NKT cells are found to suppress antigen-specific IgE production. The suppression appeared to be IgE specific, and was not detected in either V alpha 14 NKT- or IFN-gamma-deficient mice. Consistent with these results, we also found that ligand-activated V alpha 14 NKT cells inhibited Th2 cell differentiation in an in vitro induction culture system. Thus, it is likely that activated V alpha 14 NKT cells exert a potent inhibitory effect on Th2 cell differentiation and subsequent IgE production by producing a large amount of IFN-gamma. In marked contrast, our studies have revealed that IL-4 produced by V alpha 14 NKT cells has only a minor effect on Th2 cell differentiation.