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

Abstract

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-gamma and, to a lesser degree, TGF-beta1, 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-gamma 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.

• Authors: Jian Hong, Ningli Li, Xuejun Zhang, Biao Zheng, Jingwu Z Zhang
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 102 Issue 18 Pg. 6449-54 (May 03 2005) ISSN: 0027-8424 [Print] United States
• PMID: 15851684 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• DNA Primers
• DNA-Binding Proteins
• FOXP3 protein, human
• Forkhead Transcription Factors
• Foxp3 protein, mouse
• Peptides
• Receptors, Interleukin-2
• TGFB1 protein, human
• Tgfb1 protein, mouse
• Transforming Growth Factor beta
• Transforming Growth Factor beta1
• Glatiramer Acetate
• Interferon-gamma

Topics

• Animals
• CD4-Positive T-Lymphocytes (immunology, metabolism)
• DNA Primers
• DNA-Binding Proteins (immunology, metabolism, therapeutic use)
• Forkhead Transcription Factors
• Gene Expression Regulation
• Glatiramer Acetate
• Humans
• Immunotherapy (methods)
• Interferon-gamma (metabolism)
• Leukocytes, Mononuclear (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Multiple Sclerosis (immunology, therapy)
• Peptides (immunology, metabolism)
• Receptors, Interleukin-2 (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Transforming Growth Factor beta (metabolism)
• Transforming Growth Factor beta1