Regulatory and effector T cell activation levels are prime determinants of in vivo immune regulation

Little is known about the in vivo conditions in which CD4(+)CD25(+) regulatory T cells (T,,g) exert their suppressive effect in nonlymphopenic mice. To this end, we analyzed T-reg-mediated suppression of expansion and cytokine production at different levels of Ag-specific CD4(+)CD25(-) T cell activation. Using Ab-mediated depletion of endogenous T-reg, we show that basal immunosuppression is dependent on effector T cell activation. These polyclonal T-reg, which were poorly activated in our immunization conditions, were effective in weak but not high T cell activation context. In contrast, the same immunization conditions led to proliferation of cotransferred Ag-specific T-reg. Those efficiently inhibited T cell proliferation and cytokine production even in strong T cell activation context. Interestingly, T-reg selectively suppressed expansion or cytokine production depending on the experimental approach. The importance of the immune context for efficient suppression is further supported by the observation that T-reg depletion exacerbated diabetes of NOD mice only at the early stage of the disease. Overall, our study suggests that T-reg-mediated suppression depends on the relative activation of T-reg and effector T cells in vivo. This balance may be a critical factor in the regulation of immune responses.