In normal mice a subpopulation of CD4 T cells constitutively expresses the IL-2 receptor α chain (CD25). This natural CD4 CD25⁺ subset is thymus-born, constitutively expresses IL-10 mRNA,does not produce IL-2 and is resistant to apoptosis. These cells behave as regulatory T cells inthe control of self-tolerance, inflammatory reactions and T cell homeostasis. The mechanisms by which natural CD4 CD25⁺ cells control the immune response is unclear. We examinedCD25-deficient mice, which over-express various cytokines, including proinflammatory molecules, after bacterial superantigen stimulation in vivo. We observed that this abnormal cytokine production could be controlled by the injection of natural CD4 CD25⁺ T cells and that IL-10 production is needed, as CD4 CD25⁺ T cells from IL-10 knockout mice do not correct cytokine over-production in vivo. As the circulating IL-10 produced by CD25-deficient mice was ineffective, we deduced that the key source of IL-10 was the regulatory T cell population. IL-10 is also involved in the control of cytokine production by normal T cells. However, the target of IL-10 in this control is undefined. Whether it acts directly on the effector T cells or on the regulatory CD4 CD25⁺ T cells themselves to induce their functional maturation has to be clarified.