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.