INVOLVEMENT OF NK1(-CELLS AND THEIR IFN-GAMMA PRODUCTION IN THE GENERALIZED SHWARTZMAN REACTION() T)

IL-12 (or LPS) priming and subsequent challenge by LPS produces the ge neralized Shwartzman reaction, IFN-gamma induced by IL-12 is a crucial cytokine in the priming phase. In vivo depletion of both NK cells and NK1(+) alpha beta T cells of mice by anti-NK1.1 Ab greatly reduced th e elevation of serum IFN-gamma induced by IL-12 and significantly redu ced mortality after subsequent injection of LPS, whereas depletion of NK cells alone by anti-asialo GM1 Ab only partially decreased serum IF N-gamma, and lethality was not changed, Cell sorting and culture exper iments confirmed that liver NK1(+) alpha beta T cells of IL-12-injecte d mice produced greater amounts of IFN-gamma than did liver NK cells, MHC class I-deficient mice of C57BL/6 background, which lack a majorit y of NK1(+) alpha beta T cells, produced low amounts of IFN-gamma by I L-12; no mortality was observed after the LPS challenge, However, prod uction of TNF-alpha in the second phase (after LPS challenge) was not inhibited by depletion of NK cells alone or both subsets. IL-12 and su bsequent LPS challenge activated NK1(+) alpha beta T cells in the live r and induced strong cytotoxicity of these cells not only against tumo r cells (including Fas-negative tumors) but also against a syngeneic h epatocyte cell line, Our findings show that IFN-gamma produced by NK1( +) alpha beta T cells is essential for the IL-12 priming of the Shwart zman reaction, and the autoreactivity of NK1(+) alpha beta T cells in the liver is involved in the hepatic disorders that are sometimes caus ed by IL-12, LPS, or the generalized Shwartzman reaction.