Induction of CD4+CD25+Regulatory T Cells by Copolymer-I through Activation of Transcription Factor Foxp3

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 102; no. 18; pp. 6449 - 6454
• Main Authors: Hong, Jian, Li, Ningli, Zhang, Xuejun, Zheng, Biao, Zhang, Jingwu Z., Chen, Zhu
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 03.05.2005; National Acad Sciences
• Subjects: Animals; Antibodies; Biological Sciences; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Cell lines; Cultured cells; Cytokines; DNA Primers; DNA-Binding Proteins - immunology; DNA-Binding Proteins - metabolism; DNA-Binding Proteins - therapeutic use; Forkhead Transcription Factors; Gene expression; Gene Expression Regulation; Glatiramer Acetate; Government regulation; Humans; Immunology; Immunotherapy - methods; Inductive reasoning; Interferon-gamma - metabolism; Knockout mice; Leukocytes, Mononuclear - metabolism; Messenger RNA; Mice; Mice, Inbred C57BL; Mice, Knockout; Multiple sclerosis; Multiple Sclerosis - immunology; Multiple Sclerosis - therapy; Peptides - immunology; Peptides - metabolism; Polymers; Receptors, Interleukin-2 - metabolism; Reverse Transcriptase Polymerase Chain Reaction; T cell receptors; T lymphocytes; Transcription factors; Transforming Growth Factor beta - metabolism; Transforming Growth Factor beta1
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0502187102

Copolymer-I (COP-I) has unique immune regulatory properties and is a treatment option for multiple sclerosis (MS). This study revealed that COP-I induced the conversion of peripheral CD4+CD25-to CD4+CD25+regulatory T cells through the activation of transcription factor Foxp3. COP-I 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 COP-I 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 COP-I was mediated through its ability to produce IFN-γ and, to a lesser degree, TGF-β1, 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 COP-I significantly raised the level of Foxp3 expression in CD4+T cells and promoted conversion of CD4+CD25+regulatory T cells in wild-type B6 mice but not in IFN-γ knockout mice. This study provides evidence for the role and mechanism of action of COP-I in the induction of CD4+CD25+regulatory T cells in general and its relevance to the treatment of MS.