Pancreatic islets of diabetic patients can be infiltrated, destroyed, or dysfunctional, which renders them unable to produce insulin. Therefore, as a potential cure, islets from nondiabetic donors are transplanted using immunosuppressive regimens. The Edmonton protocol had shown the most promise so far, although recently it became clear that most islet grafts are lost after 5 years (5). In this issue of the JCI, Monti et al. (6) now show that the Edmonton protocol of immunosuppression with daclizumab, rapamycin, and FK506 results in lymphopenia and thus homeostatic expansion of autoreactive CD8⁺ T cells. Lymphopenia elicits production of IL-7 and IL-15 that drives homeostatic peripheral expansion of memory T cells, which comprise autoreactive, alloreactive, and probably other T cell populations. In addition, the lack of IL-2 and blockade of the IL-2 signaling pathway might affect not only effector T cells, but also Tregs. The reemerging autoreactive T cells are capable of destroying the patient’s remaining β cells (brown) and the donor islets (blue), which are transplanted via the hepatic portal vein. It is unknown whether enhanced homeostatic proliferation of Tregs with different immunosuppressive regimens or augmentation of islet-specific Tregs after vaccination or cell transfer could be sufficient to inhibit any of the β cell–destructive T cell responses.