Chronic exposure to superantigen induces regulatory CD4 super(+) 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 sub(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 SEB-reactive T cells (and reversibly from SEB- to SEA-specific T cells) in C57BL/6 mice but not in BALB/c mice. Since C57BL/6 mice, unlike BALB/c mice, possess TCR V sub( beta )3 super(+) and V sub( beta )11 super(+) T cells able to react with both SEA and SEB, we hypothesized that SAg-unresponsive V sub( beta )3 super(+) and V sub( beta )11 super(+) 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 SEB were tested for their capacity to suppress the response of normal BALB/c cells to SEB. The production of both IFN- gamma and IL-2 following SEB stimulation was greatly impaired in co-cultures containing CD4 super(+) T cells, but not CD8 super(+) T cells, isolated from unresponsive animals. In vivo, the production of both IFN- gamma 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 SEB, SAg-reactive CD4 super(+) 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 super(+) T cells capable of suppressing SAg-reactive naive T cells.