Essential role for natural killer cells in the lethal lipopolysaccharide-induced Shwartzman-like reaction in mice

Observations in our laboratory have provided evidence that interferon-gamma (IFN-gamma) is a key regulator of inflammatory responses to bacterial lipopolysaccharide (LPS) (Heremans et al., J. Exp. Med. 1990. 171: 1853): treatment of mice with neutralizing monoclonal antibody against IFN-gamma was found to completely prevent lethal shock reactions, in particular the generalized Shwartzman reaction, whereas treatment with IFN-gamma sensitized the mice to the development of such reactions. Since activated T cells and natural killer (NK) cells are the main if not the only potential source of LPS-induced IFN-gamma, we investigated the relative importance of these cells in the development of the generalized Shwartzman-like reaction in mice by depleting them selectively with relevant monoclonal antibodies. Treatment with antibodies directed against the CD4+ T cells subset was not effective in protecting mice. Anti-CD8 antibody did attenuate the reaction to some extent. However, markedly reduced mortality was seen in mice which were depleted of NK cells by systemic administration of polyclonal anti-asialo GM1 or monoclonal anti-NK1.1 antibodies. Failure of T cells to promote the Shwartzman reaction was also evidenced by the observation that thymus-less nude mice, which are deficient in T cells, were more rather than less sensitive to the reaction. Approximately 20 times less LPS was needed to induce the lethal reaction in these mice than in NMRI mice and 58 times more anti-IFN-gamma antibody was required to block mortality. Nu/nu mice reportedly have an over-active NK cell compartiment. IFN-gamma production by these cells in LPS-treated mice may account for the augmented sensitivity. Our data suggest that NK cells may be the most important source of endogenous IFN-gamma which mediates the LPS-induced lethal reactions in mice.