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Enhancement of the synthetic ligand‐mediated function of liver NK1.1Ag+ T cells in mice by interleukin‐12 pretreatment

We previously reported that mouse NK1.1 Ag+ T (NKT) cells activated by interleukin‐12 (IL‐12) act as anti‐tumour/anti‐metastatic effectors. However, IL‐12 reportedly induces a rapid disappearance of liver NKT cells by activation‐induced apoptosis. In the present study, however, we show that injection of IL‐12 into mice merely down‐regulates the NK1.1 expression of liver NKT cells and Vβ8+ intermediate T‐cell receptor cells and CD1d/α‐galactosylceramide (α‐GalCer)‐tetramer reactive cells in the liver remained and did not decrease. Furthermore, when IL‐12‐pretreated (24 hr before) mice were injected with α‐GalCer, not only serum interferon‐γ but also serum IL‐4 concentrations increased several‐fold in comparison to the control α‐GalCer‐injected mice. However, IL‐12 pretreatment markedly up‐regulated serum ALT levels and Fas‐ligand expression on NKT cells after α‐GalCer injection in middle‐aged mice only. Consistently, the liver mononuclear cells (MNC) from IL‐12‐pretreated mice stimulated with α‐GalCer in vitro produced much greater amounts of interferon‐γ and IL‐4, and also showed a more potent cytotoxicity against tumour targets than those from mice pretreated with phosphate‐buffered saline. Liver MNC from middle‐aged mice, but not from young mice pretreated with IL‐12, also showed increased cytotoxicity following in vitroα‐GalCer stimulation against cultured hepatocytes. Furthermore, IL‐12 treatment of middle‐aged mice enhanced tumour necrosis factor receptor 1 mRNA expression in liver Vβ8+ T cells, and in vitro experiments also revealed that IL‐12 pretreatment of liver MNC from middle‐aged mice enhanced their tumour necrosis factor‐α production after α‐GalCer stimulation. Synthetic ligand‐mediated functions of NKT cells, including IL‐4 production, are thus enhanced by IL‐12 pretreatment.