T(H)1 cells trigger tumor necrosis factor alpha-mediated hypersensitivity to Pseudomonas aeruginosa after adoptive transfer into SCID mice

Abstract

Recent experiments have shown that gamma interferon (IFN-γ), either administered or induced in vivo, e.g., by certain bacteria, is a key mediator in inducing hypersensitivity to bacterial lipopolysaccharides. The source of endogenous IFN-γ in this context (natural killer versus T(H)1 cells) has not been investigated yet. In order to investigate the role of antigen-specific, IFN-γ-producing T(H)1 cells in murine Pseudomonas aeruginosa infection, a murine T(H)1 cell fine was propagated in vitro by using recombinant P. aeruginosa outer membrane protein I. Adoptive transfer experiments were performed by intravenous injection of various amounts of T(H)1 cells into P. aeruginosa-challenged SCID mice. Adoptive transfer of 5 x 106 T cells into SCID mice followed by an intraperitoneal challenge with 1.4 x 106 CFU of live P. aeruginosa resulted in the rapid death of the animals within 12 h postchallenge, whereas transfer of lower T-cell doses and saline as a control did not cause any detrimental effects. After challenge with 2.8 x 106 CFU of P. aeruginosa, similar results were obtained 18 h postchallenge; however, at the end of the 72-h observation period, no significant differences in survival rates were obtained between the groups treated with different amounts of T cells. The rapid death of mice treated with 5 x 106 T cells was reflected by 860-fold-elevated levels of tumor necrosis factor alpha (TNF- α) present in serum 2 h postchallenge, whereas no significant differences in TNF-α serum levels were detectable in mice treated with lower doses of T cells or with saline. Pretreatment of T-cell-reconstituted SCID mice with neutralizing anti-IFN-γ, monoclonal antibodies completely protected mice from bacterial challenge and reduced TNF-α levels in serum. We conclude that under the experimental conditions described here. IFN-γ- and interleukin-2- producing T(H)1 cells represent an important trigger mechanism inducing TNF- α-mediated hypersensitivity to bacterial endotoxin.