Natural and Induced CD4⁺CD25⁺ Cells Educate CD4 ⁺CD25^- Cells to Develop Suppressive Activity: The Role of IL-2, TGF-β, and IL-10

Thymus-derived, natural CD4⁺CD25⁺ regulatory T cells can educate peripheral CD4⁺CD25^- cells to develop suppressive activity by poorly understood mechanisms. TGF-β has IL-2-dependent costimulatory effects on alloactivated naive, human CD4 ⁺ T cells and induces them ex vivo to become potent contact-dependent, cytokine-independent suppressor cells. In this study, we report that CD4⁺CD25⁺ cells are the targets of the costimulatory effects of IL-2 and TGF-β. These cells do not divide, but, instead, greatly increase the numbers of CD4⁺CD25^- cells that become CD25⁺ cytokine-independent suppressor cells. These CD4⁺CD25⁺ regulatory cells, in turn, induce other alloactivated CD4⁺CD25^- cells to become potent suppressor cells by mechanisms that, surprisingly, require both cell contact and TGF-β and IL-10. The suppressive effects of these secondary CD4 ⁺CD25⁺ cells depend upon TGF-β and IL-10. Moreover, both the naive CD4⁺ cells induced by IL-2 and TGF-β to become suppressor cells, and the subsequent CD4⁺CD25^- cells educated by them to become suppressors express FoxP3. We suggest that the long-term effects of adoptively transferred natural-like CD4 ⁺CD25⁺ regulatory cells induced ex vivo are due to their ability to generate new cytokine-producing CD4⁺ regulatory T cells in vivo.