Synergistic and antagonistic interactions between LPS and superantigens.

Superantigens trigger polyclonal activation of T lymphocytes with cytokine release that eventually may lead to lethal cytokine syndrome (toxic shock). In contrast, bacterial components that are recognized by Toll-like receptors (e.g. LPS or CpG DNA) primarily target macrophages and dendritic cells. We have analyzed whether superantigens and TLR ligands interact with each other. We found that superantigens synergize with LPS in an IFN-gamma-dependent pathway. More important, we found compelling evidence that superantigens prime the innate immune cell system to a subsequent challenge with endotoxin. This sensitization was critically dependent on T-cell derived IFN-gamma. When we analyzed the underlying molecular mechanisms, we additionally found that TLR stimulation enhanced IFN-gamma-mediated cellular responses. Moreover, TLR ligands induced proteins of the SOCS family thus shutting off IFN-gamma-mediated cellular activation. Since IFN-gamma is synthesized by T cells after superantigen triggering, these results show that superantigen and TLR pathways are interconnected and regulate each other. They further show that the outcome of this interaction may include activation as well as down-regulation of the respective response pattern.