The major obstacle to allogeneic islet transplantation is the immune rejection of the transplanted donor islets. The risk of chronic islet allograft rejection is reduced through the use of calcineurin inhibitors, mTOR inhibitors, steroids, and anti-proliferative drugs however heavy immunosuppression does not guarantee long-term islet allograft survival but increases rates of infection, malignancy, and renal failure. Inhibition of TNFR family costimulation pathways has been explored as a means to promote islet graft survival but few studies have resulted in delayed or long-term allograft survival in the absence of additional immunosuppression. Blockade of CD27/CD60 and OX40/OX40L interactions allowed for prolonged islet allograft and xenograft survival however CD28-blockade was a prerequisite. Administration of CD40L (CD154) blocking antibodies in the absence of additional immunosuppression allowed the long-term survival of islet allografts in non-human primates. However, the use of anti-CD40L monoclonal antibody in human clinical trials was halted due to the increased incidence of thromboembolic complications. Thus it is clear that targeting the extracellular co-stimulation molecules significantly improves islet allograft survival however safety concerns have halted progress in this field. We hypothesised that targeting intracellular signalling components of T cell costimulation pathways would be one option to bypass the detrimental thromboembolic effects, but achieve improved graft outcomes with reduced immunosuppression. Here, we report targeting TNF receptor associated factor (TRAF) 2 as a mechanism to achieve islet allograft survival with minimal immunosuppression. The data presented here forms a conceptual and preclinical framework for the targeting of intracellular mediators of costimulation.