INTERLEUKIN-12 INDUCES CYTOTOXIC NK1(-BETA T-CELLS IN THE LUNGS OF EUTHYMIC AND ATHYMIC MICE() ALPHA)

We recently reported that interleukin-12 (IL-12) stimulated hepatic NK 1.1 Ag+ alpha beta T cells with intermediate T-cell receptor (TCR; NK1 (+) TCR(int) cells) and enhanced their NK1 expression (NK1(high) TCR(i nt)), and that these cells acquire strong major histocompatibility com plex (MHC) unrestricted cytotoxicity in C57BL/6 mice, both +/+ and nu/ nu. In the present study, eve 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 cell s exhibit strong MHC unrestricted cytotoxicity against NK-sensitive an d -resistant targets. A small number of NK1(high) TCR(int) cells was a lso found in peripheral blood after increased amounts of IL-12 were ad ministered. Cytotoxicity tests ir? vitro revealed that the cytotoxic a ctivity 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 populat ion not only in the liver but also in the lung of mice. IL-12 injectio n into mice markedly elevates serum interferon-gamma (IFN-gamma) level s, However, although IL-12-induced cytotoxicity of NK1(high) TCR(int) cells was significantly reduced by anti-IFN-gamma antibody injection ( which decreased serum IFN-gamma to an undetectable level), the appeara nce of NK1(high) TCR(int) cells in the lung and liver was not so affec ted. These results suggest that IFN-gamma is an important mediator of the cytotoxicity of NK1(high) TCR(int) cells but is not an essential f actor for induction of these cells. We also added data showing that IL -12 has a broad antimetastatic effect against various liver and lung m etastatic tumours intravenously injected into several strains of mice, including NK-deficient bg/bg mice. It can be considered that, in addi tion to NK cells, CD8(+) cytotoxic T cells and gamma delta T cells, NK 1(+) TCR(int) cells can be categorized as one of the cytotoxic effecto r populations. These novel type cells distinct from regular T cells ma y play an important role in monitoring intra- and perivascular areas.