Susceptibility to multiple autoimmune diseases is associated with common gene polymorphisms influencing IL-2 signaling and T_reg function, making T_reg-specific expansion by IL-2 a compelling therapeutic approach to treatment. As an in vivo IL-2 half-life enhancer we used a non-targeted, effector-function-silent human IgG1 as a fusion protein. An IL-2 mutein (N88D) with reduced binding to the intermediate affinity IL-2Rβγ receptor was engineered with a stoichiometry of two IL-2N88D molecules per IgG, i.e. IgG-(IL-2N88D)₂. The reduced affinity of IgG-(IL-2N88D)₂ for the IL-2Rβγ receptor resulted in a T_reg-selective molecule in human whole blood pSTAT5 assays. Treatment of cynomolgus monkeys with single low doses of IgG-(IL-2N88D)₂ induced sustained preferential activation of T_regs accompanied by a corresponding 10–14-fold increase in CD4⁺ and CD8⁺ CD25⁺FOXP3⁺ T_regs; conditions that had no effect on CD4⁺ or CD8⁺ memory effector T cells. The expanded cynomolgus T_regs had demethylated FOXP3 and CTLA4 epigenetic signatures characteristic of functionally suppressive cells. Humanized mice had similar selective in vivo responses; IgG-(IL-2N88D)₂ increased T_regs while wild-type IgG-IL-2 increased NK cells in addition to T_regs. The expanded human T_regs had demethylated FOXP3 and CTLA4 signatures and were immunosuppressive. These results describe a next-generation immunotherapy using a long-lived and T_reg-selective IL-2 that activates and expands functional T_regs in vivo. Patients should benefit from restored immune homeostasis in a personalized fashion to the extent that their autoimmune disease condition dictates opening up the possibility for remissions and cures.