CD25^- T cells generate CD25⁺Foxp3⁺ regulatory T cells by peripheral expansion

Naturally occurring CD4⁺ regulatory T cells arc generally identified through their expression of CD25. However, in several experimental systems considerable T_reg activity has been observed in the CD4 ⁺CD25^- fraction. Upon adoptive transfer, the expression of CD25 in donor-derived cells is not stable, with CD4⁺CD25⁺ cells appearing in CD4⁺CD25^- T cell-injected animals and vice versa. We show in this study that CD25⁺ cells arising from donor CD25^- cells upon homeostatic proliferation in recipient mice express markers of freshly isolated T_reg cells, display an anergic state, and suppress the proliferation of other cells in vitro. The maintenance of CD25 expression by CD4⁺CD25⁺ cells depends on IL-2 secreted by cotransferred CD4⁺CD25^- or by Ag-stimulated T cells in peripheral lymphoid organs.