Antigen-specific FoxP3-transduced T-cells can control established type 1 diabetes.
CD4(+)CD25(+) T-cells can be used to interfere with spontaneous autoimmune diseases such as type 1 diabetes. However, their low frequency and often unknown specificity represent major obstacles to their therapeutic use. Here we have explored the fact that ectopic expression of the transcription factor Foxp3 can confer a suppressor phenotype to naive CD4(+) T-cells. We found that retroviral transduction of polyclonal CD4 T-cells with FoxP3 was not effective in interfering with established type 1 diabetes. Thus, more subtle and more organ-specific regulation might be required to prevent type 1 diabetes, as well as to avoid systemic immunosuppression. However, a single injection of 10(5) FoxP3-transduced T-cells with specificity for islet antigen stabilized and reversed disease in mice with recent-onset diabetes. By comparing FoxP3-transduced T-cells with various antigen specificities, it became clear that the in vivo effect correlated with specific homing to and activation in pancreatic lymph nodes and not with in vitro suppressor activity or cytokine production. Our results complement recent results on in vitro-amplified antigen-specific T-cells in ameliorating type 1 diabetes and suggest that FoxP3 transduction of expanded T-cells might achieve the same goal.
Jaeckel
Elmar
E
Hannover Medical School, Department of Gastroenterology, Hepatology and Endocrinology, Carl Neuberg Str. 1, 30625 Hannover, Germany. jaeckel_elmar@yahoo.com
von Boehmer
Harald
H
Manns
Michael P
MP
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D051858:Forkhead Transcription Factors; D051379:Mice; D016688:Mice, Inbred NOD; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
D017931:DNA Primers; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D011993:Recombinant Fusion Proteins