Superantigens (SAg) are bacterial exotoxins that provoke extreme responses in the immune system; for example, the acute hyperactivation of SAg-reactive T cells that leads to toxic shock syndrome is followed within days by strong immunosuppression. The gamma interferon (IFN-γ) response is deeply affected in both extremes. The implication of IFN-γ in the pathophysiology of lethal shock induced in mice after a secondary challenge with the SAg staphylococcal enterotoxin B (SEB) prompted us to study the regulation of IFN-γ secretion and the intracellular response. We demonstrate in this study that a rechallenge with SEB becomes lethal only when given inside a critical time window after SEB priming and is associated with an increase of IFN-γ serum release 72 h after priming. However, at this time, a selective blockade of IFN-γ/STAT1 signaling develops in spleen cells, correlating with a lack of expression of the IFN-γ receptor beta subunit and STAT1 in the T-cell population. Selective blockade of the STAT1 signaling pathway-while simultaneously maintaining STAT3 signaling and expression-may be a protective mechanism that shortens IFN-γ production during the Th1 elector response. This blockade may also have consequences on switching towards a suppressor phenotype with chronic exposure to the superantigen. Copyright © 2007, American Society for Microbiology. All Rights Reserved.