Converting antigen-specific diabetogenic CD4 and CD8 T cells to TGF-beta producing non-pathogenic regulatory cells following FoxP3 transduction.
Immuno-regulatory defects, including a reduction in the number and function of regulatory T cells, play an important role in the development of autoimmune diabetes in both humans and non-obese diabetic (NOD) mice. In this study we tested the effect of introduction of FoxP3 into antigen non-specific polyclonal and antigen-specific monoclonal T cells on diabetes development in NOD mice. Transduction of FoxP3 into antigen-specific monoclonal (insulin or BDC2.5 mimotope specific) or antigen non-specific polyclonal T cells using retroviral transduction delayed or prevented diabetes development. However, transduced antigen-specific monoclonal T cells were considerably more effective than polyclonal T cells. Regulatory activity was not limited to CD4 T cells as potent diabetogenic CD8 T cells specific for insulin, were also reduced in pathogenicity by FoxP3 induction. The disease suppressive effect, in both CD4 and CD8 cells, was more evident in spontaneously diabetes-prone NOD hosts (non-lymphopenic) than in lymphopenic NOD.scid hosts. We suggest that this strategy of transducing antigen-specific CD4 or CD8 T cells may be a useful therapeutic approach in the prevention of autoimmune diabetes.
Peng
Jian
J
Section of Endocrinology, Yale University School of Medicine, 300, Cedar Street, New Haven, CT 06520, USA.
Dicker
Bridget
B
Du
Wei
W
Tang
Fengjuan
F
Nguyen
Phuong
P
Geiger
Terrence
T
Wong
F Susan
FS
Wen
Li
L
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology*; D015316:Genetic Therapy; D007328:Insulin / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D012190:Retroviridae; D014161:Transduction, Genetic; D016212:Transforming Growth Factor beta / Q000276:immunology*
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007328:Insulin; D016212:Transforming Growth Factor beta