Foxp3-expressing CD4(+)T cells under the control of INF-gamma promoter prevent diabetes in NOD mice.
Foxp3-transduced CD4(+)T-cells have been used for treating autoimmune diseases such as type I diabetes. However, while suppressing the activity of pathogenic T cells, they could suppress the activity of bystander T cells as well. Therefore more specific strategies need to be developed. We designed and tested a new strategy that involves converting pathogenic CD4(+)Th1 cells into regulatory T-cells by lentiviral transduction with Foxp3 under the control of interferon-gamma (IFN-gamma) promoter (IgammaP-Foxp3). After transduction under the IgammaP control, Foxp3 expression in diabetic CD4(+)Th1 cells was favored. IgammaP-Foxp3-transduced CD4(+)T cells were anergic in vitro to stimulation by antigen. The process of IgammaP-Foxp3-transduced CD4(+)T cells differentiating into Treg cells and Treg cells losing their phenotype and functions has the effect of significantly suppressing incidence and onset of diabetes and autoantigen-specific T cell response, while increasing/maintaining endogenous Tregs in nonobese diabetic (NOD) mice recipients. In this manner, CD4(+)T cells of greater specificity were developed by transducing pathogenic CD4(+)Th1 cells with Foxp3 under the control of IgammaP, in order to prevent diabetes in NOD mice. The findings of this study provide a basis for more reasonable regulatory T cells (Tregs)-based therapy, with autoimmunity being suppressed through indirect means known as "infectious tolerance".
Wang
Renxi
R
Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing, People's Republic of China.
Han
Gencheng
G
Wang
Jianan
J
Song
Lun
L
Chen
Guojiang
G
Xu
Ruonan
R
Yu
Ming
M
Qian
Jiahua
J
Shen
Beifen
B
Li
Yan
Y
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control*; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics*; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D011401:Promoter Regions, Genetic / Q000235:genetics*
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007371:Interferon-gamma