Induction of CD4+CD25+ regulatory T cells by copolymer-I through activation of transcription factor Foxp3.
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.
Hong
Jian
J
Joint Immunology Laboratory of Institute of Health Sciences and Shanghai Institute of Immunology, Chinese Academy of Sciences and Shanghai Second Medical University, Shanghai 200025, China.
Li
Ningli
N
Zhang
Xuejun
X
Zheng
Biao
B
Zhang
Jingwu Z
JZ
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism* / Q000627:therapeutic use; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation; D000068717:Glatiramer Acetate; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000276:immunology* / Q000628:therapy; D010455:Peptides / Q000276:immunology / Q000378:metabolism*; D015375:Receptors, Interleukin-2 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D017931:DNA Primers; D004268:DNA-Binding Proteins; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D010455:Peptides; D015375:Receptors, Interleukin-2; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000068717:Glatiramer Acetate; D007371:Interferon-gamma