Summary: It is now well-established that CD4+ regulatory T cells are instrumental in controlling immune responses both to self-antigens and to non-self-antigens. However, the precise modalities involved in their differentiation and survival, their mode of action and their antigen specificity are only partially understood. We have been particularly interested in the study of regulatory T cells controlling autoimmune insulin-dependent diabetes. Here, we provide evidence to support the phenotypic and functional diversity of regulatory T cells mediating transferable ‘active’ or ‘dominant’ peripheral tolerance in the non-obese diabetic mouse model (NOD). They include natural and adaptive regulatory T cells that are operational both in unmanipulated NOD mice and in animals undergoing treatments aimed at inducing/restoring tolerance to self-β-cell antigens. At least in our hands, the differential cytokine-dependency appears as a major distinctive feature of regulatory T cells subsets. Among immunoregulatory cytokines, transforming growth factor-β(TGF-β) appeared to play a key role. Herein we discuss these results and the working hypothesis they evoke in the context of the present literature, where the role of TGF-β-dependent T-cell-mediated immunoregulation is still debated.