Peptides That Mimic a T-Cell Receptor May Prevent Toxic Shock Syndrome

Blocking the binding of bacterial superantigens to specific T-cell surface receptors may be a way to prevent potentially fatal toxic shock syndrome.

Superantigens (SAgs) are a class of antigens, which cause nonspecific activation of T-cells resulting in polyclonal T cell activation and massive cytokine release. SAgs can be produced by pathogenic microbes (including viruses, mycoplasma, and bacteria) as a defense mechanism against the immune system. Compared to a normal antigen-induced T-cell response where 0.001% to 0.0001% of the body’s T-cells are activated, these SAgs are capable of activating up to 20% of the body’s T-cells. The large number of activated T-cells secretes massive amounts of cytokines (the most important of which is TNF-alpha (tumor necrotic factor-alpha)). TNF-alpha is particularly important as a part of the body's inflammatory response and in normal circumstances (where it is released locally in low levels) helps the immune system defeat pathogens. However, when it is systemically released in the blood and in high levels, it can cause severe and life-threatening symptoms, including shock and multiple organ failure.

Investigators at the Hebrew University of Jerusalem (Israel) have been studying how superantigen toxins engage the immune system. Their work was based on the understanding that in order to act, a superantigen must first bind to the CD28 protein receptor on the surface of the human immune cell. CD28 (Cluster of Differentiation 28) is one of the molecules expressed on T cells that provide co-stimulatory signals, which are required for T cell activation.

The investigators reported in the September 13, 2011, online edition of the journal PLoS Biology that to elicit inflammatory cytokine gene expression and toxicity, superantigens must bind directly into the dimer interface of CD28. Preventing access of the superantigen to CD28 was sufficient to block its lethality. Mice were protected from lethal superantigen challenge by short peptides that mimicked the structure of the CD28 dimer interface and by peptides selected to compete with the superantigen for its binding site in CD28.

These findings provide a novel therapeutic approach against toxic shock. Since the blocking peptides mimic a human cellular structure, resistance cannot arise in the infecting bacteria or in the toxins because the peptides mimic a human immune receptor that is constant and will not change.

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Hebrew University of Jerusalem