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Expansion of Functional Endogenous Antigen-Specific CD4⁺CD25⁺ Regulatory T Cells from Nonobese Diabetic Mice¹

Emma L. Masteller^*, Matthew R. Warner^*, Qizhi Tang^*, Kristin V. Tarbell^2,, Hugh McDevitt and Jeffrey A. Bluestone^3,*

^* Diabetes Center, Department of Medicine, University of California, San Francisco, CA 94143; and Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94395

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

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