I slet transplantation can temporarily cure type 1 diabetes mellitus (T1DM) but requires simultaneous immunosuppression to avoid allograft rejection. In this issue of the JCI, Monti et al. report that immune conditioning via use of the Edmonton protocol — a treatment approach in which T1DM patients infused with pancreatic islets from multiple cadaveric donors simultaneously receive immunosuppressive drugs — results in lymphopenia that is associated with elevated serum levels of the homeostatic cytokines IL-7 and IL-15, which causes in vivo expansion of the autoreactive CD8⁺ T cell population (see the related article beginning on page 1806). Reemergence of autoreactivity is likely the main culprit underlying long-term islet graft failure, and new strategies will need to be tested to circumvent this homeostatic expansion and recurrent autoreactivity.