Superantigen-induced CD4 T cell tolerance mediated by myeloid cells and IFN-gamma

We have previously shown that systemic staphylococcal enterotoxin A (SEA) i njections cause CD4 T cells in TCR-transgenic mice to become tolerant to su bsequent ex vivo restimulation. An active IFN-gamma -dependent mechanism of suppression was responsible for the apparent unresponsiveness of the CD4 T cells. In this study, me analyze the response of CD4 T cells isolated thro ughout the first 10 days of the in vivo response to injected SEA. We show t hat CD4 T cells isolated at the peak of the in vivo response undergo very l ittle activation-induced cell death after sterile FAGS sorting or restimula tion in the presence of neutralizing Abs to IFN-gamma, We also show that th e IFN-gamma -dependent tolerance develops soon after SEA injection in the s pleens of both normal and TCR-transgenic mice. This suppression is dependen t upon myeloid cells from the SEA-treated mice and is optimal when inducibl e NO synthase activity and reactive oxygen intermediates are both present. The data indicate that IFN-gamma, myeloid cells, and a combination of NO an d reactive oxygen intermediates all contribute to a common pathway of T cel l death that targets activated or responding CD4 T cells. Sorted Gr-1(+) ce lls from SEA-treated mice also directly suppress the response of naive CD4 T cells in mixed cultures, indicating that this tolerance mechanism may pla y a role in down-regulating other vigorous immune responses.