Staphylococcal toxic shock syndrome toxin 1 (TSST-1) is the major cause of toxic shock syndrome and is important in the pathophysiology of staphylococcal septic shock. Our study about the biological effects of TSST-1 in the rabbit 3 and 6 h and 7 days postinjection provides evidence that TSST-1 induces leukopenia, lymphopenia, and monocytopenia as a result of extravasation of cells in a Vss-unrestricted manner. Cells in the circulation, reduced significantly in numbers, show the same phenotypic distribution as before TSST-1 injection. Three hours post-in vivo TSST-1 injection, we demonstrated compartmentalization of the response. By quantitative RT-PCR, the induction of mRNA expression of TH1 and inflammatory cytokines in the spleen and lung and a complete lack of induction in PBMC could be shown. Proliferation assays revealed that 3 h after TSST-1, PBMC were neither activated nor responsive to in vitro restimulation, even when IL-2 was added. In contrast, 7 days later, PBMC and spleen cells were anergic: showing no response to TSST-1 but a vigorous response upon addition of IL-2. The results presented extend our understanding of the pathophysiology of toxic and septic shock as a result of superantigen toxin-producing Staphylococcus aureus. Demonstration of compartmentalization of the response proves that erroneous conclusions could be drawn by the exclusive analysis of PBMCs. The results reveal further that in nonresponsiveness to the antigen, different immunological mechanisms may be operational. Measurements of the induction of cytokine gene activation provide important complementary information to that of serum cytokine levels.