Durable control of autoimmunity requires sustained stimulation of regulatory T cells.

Intensive efforts are ongoing to promote regulatory T cells (Tregs) as a therapy for autoimmune diseases. Here, we show that a sustained increase in Tregs is required for long-term normal glycemia in a mouse model of type 1 diabetes. Efficacy was reduced when Treg increases were intermittent. A continuous Treg increase optimally preserved β cell function by more effective reduction in multiple subsets of islet-associated T effector cells, including reduced clonal expansion of autoantigen-specific T cells. Normal glycemia was associated with an islet landscape dominated by Tregs, type 2 innate lymphoid cells (ILC2s), and cytokine-producing natural killer cells, all with characteristics of regulatory cells. Our study supports the notion that robust control of autoimmunity depends on resetting the immune system to achieve a constant prolonged increase in the Treg-to-T effector cell ratio.