There is an increasing amount of knowledge on the functional properties of regulatory T cells (Treg) in the adult immune system, but data on the generation and function of these cells during human embryonic development are scarce. In this study, we show that in the fetal thymus, double‐positive cells initiate expression of CD25, GITR, CTLA4 and CD122 during their transition from the CD27^– to the CD27⁺ stage. Moreover, CD4⁺CD25⁺ fetal thymocytes already have the potential to suppress proliferation of CD25^– cells. After leaving the thymus, FoxP3⁺CD4⁺CD25⁺ Treg enter the fetal lymph nodes and spleen, where they acquire a primed/memory phenotype. A model is proposed for the development of human fetal Treg that encompasses two sequential maturation steps: initiation of a regulatory phenotype and suppressive activity in the thymus; and subsequent activation within the peripheral lymphoid organs. Upon activation, FoxP3⁺CD4⁺CD25⁺ Treg suppress potentially deleterious responses by autoreactive lymphocytes and maintain homeostasis within the developing fetus.

See accompanying Commentary: http://dx.doi.org/10.1002/eji.200525996