Temporal Sequence and Functional Implications of Vβ‐Specific T Cell Receptor Down‐regulation and Costimulatory Molecule Expression following In Vitro Stimulation with the Staphylococcal Superantigen Toxic Shock Syndrome Toxin–1

The superantigen toxic shock syndrome toxin-1 (TSST-1) is implicated as the major cause of staphylococcal toxic shock syndrome. The temporal sequence of early signaling events in human peripheral blood mononuclear cells following TSST-1 stimulation was examined. TSST-1 induced rapid and complete down-regulation of V beta 2-specific T cell receptor (TCR), followed by transient CD154 expression on CD4(+) lymphocytes. This was sequentially followed by the up-regulation of CD86, CD80, CD40, and human leukocyte antigen-DR expression on CD14(+) monocytes. In contrast, S14N, a TSST-1 mutant toxin with a single amino acid substitution that is known to be impaired in interleukin (IL)--2, interferon (IFN)-gamma, and tumor necrosis factor (TNF)-alpha secretion, was deficient in both V beta 2-TCR down-regulation and CD154 and CD80/CD86 expression. Furthermore, pretreatment with monoclonal antibodies against V beta 2-TCR, CD80/CD86, and CD154 significantly inhibited TSST-1-induced IL-2, IFN-gamma, and TNF-alpha secretion. Taken together, these results indicate that early V beta-specific TCR activation, along with CD80/CD86 and CD154 costimulation, are key determinants of the TSST-1-induced proinflammatory cytokine response.