Interleukin-12 induces cytotoxic NK1⁺ αβ T cells in the lungs of euthymic and athymic mice

We recently reported that interleukin-12 (IL-12) stimulated hepatic NK1.1 Ag⁺ αβ T cells with intermediate T-cell receptor (TCR; NK1⁺ TCR(int) cells) and enhanced their NK1 expression (NK1(high) TCR(int)), and that these cells acquire strong major histocompatibility complex (MHC) unrestricted cytotoxicity in C57BL/6 mice, both +/+ and nu/nu. In the present study, we find that although murine lung normally has few NK1⁺ TCR(int) cells. NK1(high) TCR(int) cells are induced in +/+ and nu/nu mice after systemic administration of IL-12; these cells exhibit strong MHC unrestricted cytotoxicity against NK-sensitive and -resistant targets. A small number of NK1(high) TCR(int) cells was also found in peripheral blood after increased amounts of IL-12 were administered. Cytotoxicity tests in vitro revealed that the cytotoxic activity of the lung mononuclear cells (MNC) of C57BL/6 mice induced by IL-12 was abrogated by the depletion of either NK1⁺ or CD3⁺ cells, but not of CD8⁺ cells, as reportedly was the case of hepatic MNC, suggesting that NK1(high) TCR(int) cells are an antimetastatic population not only in the liver but also in the lung of mice. IL-12 injection into mice markedly elevates serum interferon-γ (IFN-γ) levels. However, although IL-12-induced cytotoxicity of NK1(high) TCR(int) cells was significantly reduced by anti-IFN-γ antibody injection (which decreased serum IFN-γ to an undetectable level), the appearance of NK1(high) TCR(int) cells in the lung and liver was not so affected. These results suggest that IFN-γ is an important mediator of the cytotoxicity of NK1(high) TCR(int) cells but is not an essential factor for induction of these cells. We also added data showing that IL-12 has a broad antimetastatic effect against various liver and lung metastatic tumours intravenously injected into several strains of mice, including NK-deficient bg/bg mice. It can be considered that, in addition to NK cells, CD8⁺ cytotoxic T cells and γδ T cells, NK1⁺ TCR(int) cells can be categorized as one of the cytotoxic effector populations. These novel type cells distinct from regular T cells may play an important role in monitoring intra- and perivascular areas.