Inefficient peripheral tolerance of autoreactive T cells maintained by CD4+CD25+FOXP3+ T regulatory cells (Treg) is thought to contribute to the pathogenesis of autoimmune diseases including type I diabetes (T1D). Uncontrolled activation and expansion of autoreactive T cells occurs in an IL-7 and Il-15 rich environment such as after pancreatic islet transplantation. We previously showed that IL-7 can also abrogate Treg function. Here, we further explored the possibility that IL-15 may affect the function of Treg. We found that IL-15 can revert the anergic state of naïve Treg in the presence of artificial TCR stimulus. The persistent presence of IL-15 abrogated Treg mediated suppression of αCD3αCD28 bead induced T effector proliferation as well as antigen-driven and allogeneic responses of CD4+ and CD8+ T cells. Notably, the presence of IL-15 did not influence Treg suppression of CD69 and CD154 activation marker expression on activated T effector cells. We suggest that prolonged periods of homeostatic expansion with increased availability of IL-7 and IL-15 can temporarily release natural regulatory control on T cells thereby providing an additional mechanism for initiating and expanding autoreactive T cells. Our findings have implications for therapies involving lympho-depletion.