Evidence has been accumulated to demonstrate that “natural” Tregs, whose major function is to control autoimmune responses, stem as a separate lineage in the thymus. These natural Tregs are CD4⁺, they express the transcription factor Foxp3, which represents a lineage marker, and high levels of CD25. Natural Tregs that migrate to the periphery keep their phenotypic and functional properties, which are essentially cytokine independent. In parallel, other subsets of CD4⁺ Tregs have been described that very effectively control immune responses not only to self antigens but also to a wide variety of nonself antigens (microbial, tumoral, and transplantation antigens). These Tregs are not present as such in the thymus; they derive from peripheral precursors that are CD4⁺CD25^– and differentiate into functional Tregs following adequate stimulation (in the presence of the cognate antigen and specialized immunoregulatory cytokines, i.e., TGF-β, IL-10, and IL-4). They are generally termed “adaptive” Tregs. Once differentiated, adaptive Tregs, like natural Tregs, may express CD25 and Foxp3. However, one main feature that differentiates adaptive from natural Tregs is their unique cytokine dependence. The study by Vukmanovic-Stejic et al. in this issue of the JCI (14) proposes that, in humans, even at a very advanced age, adaptive Tregs essentially emerge from CD4⁺CD25^– T cells belonging to the memory T cell pool (previously primed by cognate antigens). Presently, one cannot exclude, however, that especially in young adults, some adaptive Tregs may emerge from naive, peripheral CD4⁺CD25^– T cells. Tr1, Treg type 1.