Critical Role of TGF-β and IL-2 Receptor Signaling in Foxp3 Induction by an Inhibitor of DNA Methylation.

Under physiological conditions, CD4 regulatory T (Treg) cells expressing the transcription factor Foxp3 are generated in the thymus [thymus-derived Foxp3 Treg (tTregs) cells] and extrathymically at peripheral sites [peripherally induced Foxp3 Treg (pTreg) cell], and both developmental subsets play non-redundant roles in maintaining self-tolerance throughout life. In addition, a variety of experimental and modalities can extrathymically elicit a Foxp3 Treg cell phenotype in peripheral CD4Foxp3 T cells, which has attracted much interest as an approach toward cell-based therapy in clinical settings of undesired immune responses. A particularly notable example is the induction of Foxp3 expression and Treg cell activity (iTreg cells) in initially naive CD4Foxp3 T cells through T cell receptor (TCR) and IL-2R ligation, in the presence of exogenous TGF-β.