Toxic shock syndrome toxin-1-induced death is prevented by CTLA4Ig.

Lethal toxic shock syndrome (TSS) results from the MHC class II presentation of bacterial superantigens, most commonly toxic shock syndrome-1 (TSST-1), to specific TCR Vbeta-bearing T cells. This superantigen-induced stimulation of whole T cell subsets leads to the exuberant cytokine production that in turn causes the shock syndrome. Since T cell activation and cytokine production are known to be dependent upon costimulatory signals, we reasoned that interfering with costimulation could effect TSS outcome. To test that hypothesis, we evaluated the effect of CTLA4Ig, a fusion protein known to block costimulatory signaling, on TSST-1-induced responses. CTLA4Ig not only blocked TSST-1-stimulated T cell proliferation by 90% in vitro, it also strikingly ameliorated TSST-1 induced TSS in vivo. While all mice co-administered TSST-1 and control Ig died, 75% of the CTLA4Ig plus TSST-1-treated mice survived. This salutary CTLA4Ig effect correlated with markedly diminished TSST-1 induced serum levels of TNF-alpha and IFN-gamma, but TSST-1-triggered IL-2 release was not affected. Surprisingly, while CTLA4Ig treatment group survivors remained sensitive to TSS induced by an unrelated superantigen (staphylococcal enterotoxin B), they were completely resistant to a second TSST-1 challenge. Furthermore, this TSST-1 resistance could be transferred to naive C57BL/6 mice using CD8+ T cells from CTLA4Ig plus TSST-1-primed mice. These data suggest several novel interpretations: 1) that the release of TNF-alpha and IL-2 have a different costimulatory signal dependence in vivo, 2) that the TSS resistance conferred by CTLA4Ig was superantigen specific, and 3) that the delayed and transferable resistance to TSST-1 was due, at least in part, to CD8+ T cells with suppressor function.