Chronic exposure to superantigen induces regulatory CD4+ T cells with IL-10-mediated suppressive activity

The repeated injection of bacterial superantigens (SAg), such as staphylococcus enterotoxin (SE) A or B, has been shown in mice to induce a state of unresponsiveness characterized by the lack of secretion of T(h)1 lymphokines, such as IL-2 and IFN-gamma, following subsequent SAg challenge. We made the observation, in vivo as well as in vitro, that unresponsiveness to SAg could be transferred from SEA- to SEE-reactive T cells land reversibly from SEB- to SEA-specific T cells) in C57BU6 mice but not in BALB/c mice. Since C57BL/6 mice, unlike BALB/c mice, possess TCR V(beta)3(+) and V beta 11(+) T cells able to react with both SEA and SEE, we hypothesized that SAg-unresponsive V(beta)3(+) and V(beta)11(+) T cells could mediate linked suppression of other SAg-reactive T cells. To analyze further this possibility, spleen cells from BALB/c mice made unresponsive to SEE were tested for their capacity to suppress the response of normal BALB/c cells to SEE. The production of both IFN-gamma and IL-2 following SEE stimulation was greatly impaired in co-cultures containing CD4(+) T cells, but not CD8(+) T cells, isolated from unresponsive animals. In vivo, the production of both IFN-1 and IL-2 responses to SEB was dramatically reduced in animals adoptively transferred with unresponsive spleen cells. This suppression was abrogated in recipients injected with neutralizing anti-IL-10 antibodies. Moreover, in animals made unresponsive to SEE, SAg-reactive CD4(+) T cells were found to express high levels of CTLA-4, a molecule recently described to play an essential role in the suppressive function of regulatory T cells. Taken together these results demonstrate that the repetitive injection of SAg induces the differentiation of regulatory CD4+ T cells capable of suppressing SAg-reactive naive T cells.