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Regulatory T (Treg) cells mainly develop within the thymus and arise from CD25 + Foxp3 - (CD25 + TregP) or CD25 - Foxp3 + (Foxp3 + TregP) Treg cell precursors resulting in Treg cells harboring distinct transcriptomic profiles and complementary T cell receptor repertoires. The stable and long-term expression of Foxp3 in Treg cells and their stable suppressive phenotype are controlled by the demethylation of Treg cell-specific epigenetic signature genes including an evolutionarily conserved CpG-rich element within the Foxp3 locus, the Treg-specific demethylated region (TSDR). Here we analyzed the dynamics of the imprinting of the Treg cell-specific epigenetic signature genes in thymic Treg cells. We could demonstrate that CD25 + Foxp3 + Treg cells show a progressive demethylation of most signature genes during maturation within the thymus. Interestingly, a partial demethylation of several Treg cell-specific epigenetic signature genes was already observed in Foxp3 + TregP but not in CD25 + TregP. Furthermore, Foxp3 + TregP were very transient in nature and arose at a more mature developmental stage when compared to CD25 + TregP. When the two Treg cell precursors were cultured in presence of IL-2, a factor known to be critical for thymic Treg cell development, we observed a major impact of IL-2 on the demethylation of the TSDR with a more pronounced effect on Foxp3 + TregP. Together, these results suggest that the establishment of the Treg cell-specific hypomethylation pattern is a continuous process throughout thymic Treg cell development and that the two known Treg cell precursors display distinct dynamics for the imprinting of the Treg cell-specific epigenetic signature genes., (Copyright © 2019 Herppich, Toker, Pietzsch, Kitagawa, Ohkura, Miyao, Floess, Hori, Sakaguchi and Huehn.)