Natural and Induced CD4 super(+)CD25 super(+) Cells Educate CD4 super(+)CD25 super(-) Cells to Develop Suppressive Activity: The Role of IL-2, TGF- beta , and IL-10

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