Expansion of Functional Endogenous Antigen-Specific CD4+CD25+ Regulatory T Cells from Nonobese Diabetic Mice

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Abstract
CD4+CD25+Foxp3+ regulatory T cells (Treg) are critical for controlling autoimmunity. Evidence suggests that Treg development, peripheral maintenance, and suppressive function are dependent on Ag specificity. However, there is little direct evidence that the Treg responsible for controlling autoimmunity in NOD mice or other natural settings are Ag specific. In fact, some investigators have argued that polyclonal Ag-nonspecific Treg are efficient regulators of immunity. Thus, the goal of this study was to identify, expand, and characterize islet Ag-specific Treg in NOD mice. Ag-specific Treg from NOD mice were efficiently expanded in vitro using IL-2 and beads coated with recombinant islet peptide mimic-MHC class II and anti-CD28 mAb. The expanded Ag-specific Treg expressed prototypic surface markers and cytokines. Although activated in an Ag-specific fashion, the expanded Treg were capable of bystander suppression both in vitro and in vivo. Importantly, the islet peptide mimic-specific Treg were more efficient than polyclonal Treg in suppressing autoimmune diabetes. These results provide a direct demonstration of the presence of autoantigen-specific Treg in the natural setting that can be applied as therapeutics for organ-specific autoimmunity.