In vivo control of diabetogenic T-cells by regulatory CD4+CD25+ T-cells expressing Foxp3.
To understand the ability of regulatory T-cells to control diabetes development in clinically relevant situations, we established a new model of accelerated diabetes in young DP-BB rats by transferring purified T-cells from DR-BB rats made acutely diabetic. Transfer of 3, 5, 10, or 23 million pure in vitro-activated T-cells accelerated diabetes onset in >90% of the recipients, with the degree of acceleration being dosage dependent. Cotransfer of unfractionated leukocytes from healthy donors prevented diabetes. Full protection was achieved when protective cells were transferred 3-4 days before diabetogenic cells, whereas transfer 2 days before conferred only partial protection. Protection resided in the CD4(+) fraction, as purified CD4(+) T-cells prevented the accelerated diabetes. When CD25(+) cells were depleted from these cells before they were transferred, their ability to prevent diabetes was impaired. In contrast, two million CD4(+)CD25(+) cells (expressing Foxp3) prevented the accelerated diabetes when transferred both before and simultaneously with the diabetogenic T-cells. In addition, 2 million CD4(+)CD25(+) T-cells prevented spontaneous diabetes, even when given to rats age 42 days, whereas 20 million CD4(+)CD25(-) cells (with low Foxp3 expression) were far less effective. We thus demonstrated that CD4(+)CD25(+) cells exhibit powerful regulatory potential in rat diabetes.
Lundsgaard
Dorthe
D
Hagedorn Research Institute, Gentofte, Denmark.
Holm
Thomas Lindebo
TL
Hornum
Lars
L
Markholst
Helle
H
D019264:Adoptive Transfer; D000375:Aging; D000818:Animals; D015704:CD4 Antigens / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000502:physiology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000517:prevention & control*; D051858:Forkhead Transcription Factors; D015870:Gene Expression; D015759:Ionomycin; D008213:Lymphocyte Activation / Q000502:physiology; D011236:Prediabetic State; D051381:Rats; D015375:Receptors, Interleukin-2 / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000502:physiology* / Q000637:transplantation; D013755:Tetradecanoylphorbol Acetate; D014157:Transcription Factors / Q000502:physiology*
D015704:CD4 Antigens; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C500522:Foxp3 protein, rat; D015375:Receptors, Interleukin-2; D014157:Transcription Factors; D015759:Ionomycin; D013755:Tetradecanoylphorbol Acetate