Specific Immunosuppression with Inducible Foxp3-Transduced Polyclonal T cells

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Abstract
Forkhead box p3 (Foxp3)-expressing regulatory T cells are key mediators of peripheral tolerance suppressing undesirable immune responses. Ectopic expression of Foxp3 confers regulatory T cell phenotype to conventional T cells, lending itself to therapeutic use in the prevention of autoimmunity and transplant rejection. Here, we show that adoptive transfer of polyclonal, wild-type T cells transduced with an inducible form of Foxp3 (iFoxp3) can be used to suppress immune responses on demand. In contrast to Foxp3-transduced cells, iFoxp3-transduced cells home “correctly” into secondary lymphoid organs, where they expand and participate in immune responses. Upon induction of iFoxp3, the cells assume regulatory T cell phenotype and start to suppress the response they initially partook in without causing systemic immunosuppression. We used this approach to suppress collagen-induced arthritis, in which conventional Foxp3-transduced cells failed to show any effect. This provides us with a generally applicable strategy to specifically halt immune responses on demand without prior knowledge of the antigens involved. Autoimmune diseases come in many diverse forms—such as rheumatoid arthritis, type I diabetes, multiple sclerosis, and inflammatory bowel disease—yet all share the same underlying cause, the launch of a detrimental immune response. In healthy individuals, a specialized immune cell type called regulatory T cells prevents these undesirable immune responses. Here, we present a strategy to suppress undesirable immune responses using genetically modified proinflammatory T cells that participate in these inappropriate immune responses until they are activated with a drug. At this point, the genetic modification causes them to change their behavior to that of regulatory T cells. Using a mouse model, we demonstrate that this approach can be used to stop undesirable immune responses on demand with minimal intervention.

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