Induction of CD4+CD25+ regulatory T cells by copolymer-I through activation of transcription factor Foxp3

Copolymerd (COP-1) has unique immune regulatory properties and is a treatment option for multiple sclerosis (MS). This study revealed that CON induced the conversion of peripheral CD4(+)CD25(-) to CD4(+)CD25(+) regulatory T cells through the activation of transcription factor Foxp3. CON treatment led to a significant increase in Foxp3 expression in CD4(+) T cells in MS patients whose Foxp3 expression was reduced at baseline. CD4(+)CD25(+) T cell lines generated by CON expressed high levels of Foxp3 that correlated with an increased regulatory potential. Furthermore, we demonstrated that the induction of Foxp3 in CD4(+) T cells by CON was mediated through its ability to produce IFN-gamma and, to a lesser degree, TGF-beta 1, as shown by antibody blocking and direct cytokine induction of Foxp3 expression in T cells. It was evident that in vitro treatment and administration with CON significantly raised the level of Foxp3 expression in CD4(+) T cells and promoted conversion of CD4(+)CD25(+) regulatory T cells in wild-type 136 mice but not in IFN-gamma knockout mice. This study provides evidence for the role and mechanism of action of CON in the induction of CD4(+)CD25(+) regulatory T cells in general and its relevance to the treatment of MS.